AU2013243899B2 - Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof - Google Patents

Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof Download PDF

Info

Publication number
AU2013243899B2
AU2013243899B2 AU2013243899A AU2013243899A AU2013243899B2 AU 2013243899 B2 AU2013243899 B2 AU 2013243899B2 AU 2013243899 A AU2013243899 A AU 2013243899A AU 2013243899 A AU2013243899 A AU 2013243899A AU 2013243899 B2 AU2013243899 B2 AU 2013243899B2
Authority
AU
Australia
Prior art keywords
compound
alkyl
nhn
disease
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
AU2013243899A
Other versions
AU2013243899A1 (en
Inventor
John Hood
Sunil Kumar Kc
David Mark Wallace
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biosplice Therapeutics Inc
Original Assignee
Samumed LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=49292798&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AU2013243899(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Samumed LLC filed Critical Samumed LLC
Publication of AU2013243899A1 publication Critical patent/AU2013243899A1/en
Application granted granted Critical
Publication of AU2013243899B2 publication Critical patent/AU2013243899B2/en
Priority to AU2016203274A priority Critical patent/AU2016203274B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Oncology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Vascular Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Emergency Medicine (AREA)

Abstract

Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states. One embodiment disclosed herein includes a compound having the structure of Formula I:

Description

WO 2013/151708 PCT/US2013/031055 INDAZOLE INHIBITORS OF THE WNT SIGNAL PATHWAY AND THERAPEUTIC USES THEREOF RELATED APPLICATIONS Cross-Reference to Related Applications [0001] This application claims the benefit of U.S. Provisional Application No. 61/620,107, filed April 4, 2012, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Field of the Invention [00021 This invention relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of an indazole compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states. Description of the Related Art [0003] Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. Speculation on the mechanisms underlying these patterning effects usually centers on the secretion of a signaling molecule that elicits an appropriate response from the tissues being patterned. More recent work aimed at the identification of such signaling molecules implicates secreted proteins encoded by individual members of a small number of gene families. [00041 A longstanding idea in cancer biology is that cancers arise and grow due to the formation of cancer stem cells, which may constitute only a minority of the cells within a tumor but are nevertheless critical for its propagation. Stem cells are appealing as the cell of origin for cancer because of their pre-existing capacity for self 1 WO 2013/151708 PCT/US2013/031055 renewal and for unlimited replication. In addition, stem cells are relatively long-lived in comparison to other cells within tissues, providing a greater opportunity to accumulate the multiple additional mutations that may be required to increase the rate of cell proliferation and produce clinically significant cancers. Of particular recent interest in the origin of cancer is the observation that the Wnt signaling pathway, which has been implicated in stem cell self-renewal in normal tissues, upon continuous activation has also been associated with the initiation and growth of many types of cancer. This pathway thus provides a potential link between the normal self-renewal of stem cells and the aberrantly regulated proliferation of cancer stem cells. [00051 The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 7 genes identified in the human. Members of the Wnt family of signaling molecules mediate many important short-and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its important role in the inductive interactions that regulate growth and differentiation, and likely also plays important roles in the homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic p-catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin Dl. In addition, misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. More recently, the Wnt pathway has been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues that now includes skin, blood, gut, prostate, muscle and the nervous system. [00061 Pathological activation of the Wnt pathway is also believed to be the initial event leading to colorectal cancer in over 85% of all sporadic cases in the Western world. Activation of the Wnt pathway has also been extensively reported for hepatocellular carcinoma, breast cancer, ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomas and leukemias. In addition to cancer, inhibitors of the Wnt pathway can be used for stem cell research or for the treatment of any diseases characterized by aberrant Wnt activation such as diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma as well as mycotic and viral infections and bone and cartilage diseases. As such, it is a therapeutic target that is of great interest to the field. 2 WO 2013/151708 PCT/US2013/031055 [0007] In addition to cancer, there are many cases of genetic diseases due to mutations in Wnt signaling components. Examples of some of the many diseases are Alzheimer's disease [Proc. Natl. Acad Sci. U S A (2007), 104(22), 9434-9], osteoarthritis, polyposis coli [Science (1991), 253(5020), 665-669], bone density and vascular defects in the eye (osteoporosis-pseudoglioma syndrome, OPPG) [N. Engl. J. Med (2002), 346(20), 1513-21], familial exudative vitreoretinopathy [Hum. Mutat. (2005), 26(2), 104-12], retinal angiogenesis [Nat. Genet. (2002), 32(2), 326-30], early coronary disease [Science (2007), 315(5816), 1278-82], tetra-amelia syndrome [Am. J Hum. Genet. (2004), 74(3), 558-63], Mullerian-duct regression and virilization [Engl. J. Med (2004), 351(8), 792-8], SERKAL syndrome [Am. J. Hum. Genet. (2008), 82(1), 39 47], diabetes mellitus type 2 [Am. J Hum. Genet. (2004), 75(5), 832-43; N. Engl. J Med (2006), 355(3), 241-50], Fuhrmann syndrome [Am. J Hum. Genet. (2006), 79(2), 402-8], Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome [Am. J Hum. Genet. (2006), 79(2), 402-8], odonto-onycho-dermal dysplasia [Am. J. Hum. Genet. (2007), 81(4), 821 8], obesity [Diabetologia (2006), 49(4), 678-84], split-hand/foot malformation [Hum. Mol. Genet. (2008), 17(17), 2644-53], caudal duplication syndrome [Am. J Hum. Genet. (2006), 79(1), 155-62], tooth agenesis [Am. J Hum. Genet. (2004), 74(5), 1043-50], Wilms tumor [Science (2007), 315(5812), 642-5], skeletal dysplasia [Nat. Genet. (2009), 41(1), 95-100], focal dermal hypoplasia [Nat. Genet. (2007), 39(7), 836-8], autosomal recessive anonychia [Nat. Genet. (2006), 38(11), 1245-7], neural tube defects [N. Engl. J. Med (2007), 356(14), 1432-7], alpha-thalassemia (ATRX) syndrome [The Journal of Neuroscience (2008), 28(47), 12570 -12580], fragile X syndrome [PLoS Genetics (2010), 6(4), e1000898], ICF syndrome, Angelman syndrome [Brain Research Bulletin (2002), 57(1), 109-119], Prader-Willi syndrome [Journal of Neuroscience (2006), 26(20), 5383-5392], Beckwith-Wiedemann Syndrome [Pediatric and Developmental Pathology (2003), 6(4), 299-306] and Rett syndrome. [0008] Regulation of cell signaling by the Wnt signaling pathway is critical for the formation of neuronal circuits. Wnt pathway modulates in neural tissue, among other things, axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnt pathway activates and/or regulates diverse signaling pathways and other processes that lead to local changes on the cytoskeleton or global cellular 3 WO 2013/151708 PCT/US2013/031055 changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of various Wnt proteins and the localization of their receptors. Wnt pathway mediates synaptic structural changes induced by neuronal activity or experience. Evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders [Brain Research Reviews (2000), 33(1), 1-12; Oncogene (2006) 25(57), 7545-7553; Molecular Neurodegeneration (2008), 3, 9; Neurobiology of Disease (2010), 38(2), 148-153; Journal of Neurodevelopmental Disorders (2011), 3(2), 162-174 and Cold Spring Harbor Perspectives in Biology February (2012), 4(2)]. SUMMARY OF THE INVENTION [00091 The present invention makes available methods and reagents, involving contacting a cell with an agent, such as an aromatic compound, in a sufficient amount to antagonize a Wnt activity, e. g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components. [00101 Some embodiments disclosed herein include Wnt inhibitors containing an indazole core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds. [00111 One embodiment disclosed herein includes a compound having the structure of Formula I:
R
2 / N N/ \ NH N N H as well as prodrugs and pharmaceutically acceptable salts thereof. [0012] In some embodiments of Formula (I): R' is -heteroarylR 3
R
4 ; 4 WO 2013/151708 PCT/US2013/031055 R is selected from the group consisting of H, -heteroarylR 5 , -heterocyclylR 6 and -arylR 7 ; R3 is selected from the group consisting of H, -heterocyclylR , -NHC(=0)R, NHSO 2 R , -NR"R and -(C 1
-
6 alkyl)NR"R1; with the proviso that R 2 and R 3 are not both H;
R
4 is 1-3 substituents each selected from the group consisting of H, C 1 .9 alkyl, halide, -CF 3 , -CN, OR13 and amino; each R5 is independently 1-4 substituents each selected from the group consisting of H, C 1 .9 alkyl, halide, -CF 3 , -CN, OR 13 , -C(=O)R", amino and -(C 1 -6 alkyl)NR"R 12 ; each R 6 is independently 1-5 substituents each selected from the group consisting of H, C 1
.
9 alkyl, halide, -CF 3 , -CN, OR 13 and amino; each R7 is independently 1-5 substituents each selected from the group consisting of H, C 1
.
9 alkyl, halide, -CF 3 , -CN, OR 13 , amino, -(C 1
.
6 alkyl)NHSO 2 R", -NR 12 (C1-6 alkyl)NR"R1 2 and -(C 1
-
6 alkyl)NR"R1;
R
8 is 1-5 substituents each selected from the group consisting of H, C 1
.
9 alkyl, halide, -CF 3 , -CN, OR 13 and amino;
R
9 is selected from the group consisting of C 1
.
9 alkyl, -heteroarylR, heterocyclylR 6 , -arylR 7 and -CH 2 carbocyclyl;
R
1 0 is selected from the group consisting of C 1
.
9 alkyl, -heteroarylR, heterocyclylR 6 , -arylR 7 , and -carbocyclylR14 each R" is independently selected from C1- 6 alkyl; each R1 2 is independently selected from the group consisting of H and C 1
-
6 alkyl; each R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring; each R 13 is independently selected from the group consisting of H and C 1
-
6 alkyl;
R
1 4 is 1-5 substituents each selected from the group consisting of H, C 1
.
9 alkyl, halide, -CF 3 , -CN, OR 13 and amino; with the proviso that Formula I is not a structure selected from the group consisting of: 5 WO 2013/151708 PCT/US2013/031055 N ON NHNN N H - N NH _ N N NH N N H H NH H- /-NH NH NH 0 N. \NH \NH O HNH NH NN N N N N N N N H H H H O NH 0NH - 0 NH -NH N N N N N H N N d N N H HHH. N 0_ 0 NH -- N NH NH NH /N N N N N. NH NH \NH ' \NH N N N, ,N N~ N - N N~ N 'N N H H HH H /N N 0 N en i p d /n O NH NH -N NHN NH Foml (I).1 N N N N \N \N \NH \ N N NN NN copsiin N opisn -cmoudo geerl-orul N I anaphrmcetially H H HH H N N NHN 1 0 -~N H 100131 Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of general Formula (). [0014] Some embodiments include pro-drugs of a compound of general Formula (1). [0015] Some embodiments of the present invention include pharmaceutical compositions comprising a compound of general Formula (1) and a pharmaceutically acceptable carrier. [00161 Other embodiments disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a subject affected by a disorder or disease in which aberrant Wnt 6 WO 2013/151708 PCT/US2013/031055 signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to any of the above formulas. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct an genetic disorder due to mutations in Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra amelia syndrome, Mifllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome and Rett syndrome. [00171 Another embodiment disclosed herein includes a pharmaceutical composition that has a compound according to any of the above formulas and a pharmaceutically acceptable carrier, diluent, or excipient. [00181 Some embodiments of the present invention include methods to prepare a compound of general Formula (I). [00191 It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION OF THE INVENTION [00201 Compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins would be of tremendous benefit. Certain embodiments provide such compositions and methods. Certain related 7 WO 2013/151708 PCT/US2013/031055 compounds and methods are disclosed in U.S. Application Ser. No. 12/852,706, filed August 9, 2010, which claims priority to U.S. Provisional Application Ser. Nos. 61/232,603 and 61/305,459, all of which are incorporated by reference in their entirety herein. [00211 Some embodiments relate to a method for treating a disease such as cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, MUllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader Willi syndrome, Beckwith-Wiedemann Syndrome and Rett syndrome. [0022] In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by the pathological activation or mutations of the Wnt pathway. The composition includes a pharmaceutically acceptable carrier and a Wnt pathway inhibitor as described herein. Definitions [00231 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [00241 In this specification and in the claims, the following terms have the meanings as defined. As used herein, "alkyl" means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl 8 WO 2013/151708 PCT/US2013/031055 isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl and sec-pentyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, thio, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, heterocyclyl, carbocycyl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e.g., containing C=C- or -C=C- subunits), at one or several positions. Typically, alkyl groups will comprise 1 to 9 carbon atoms, preferably 1 to 6, more preferably 1 to 4, and most preferably 1 to 2 carbon atoms. [00251 As used herein, "carbocyclyl" means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms, preferably 3 to 6. [00261 As used herein, "lower alkyl" means a subset of alkyl, and thus is a hydrocarbon substituent, which is linear, or branched. Preferred lower alkyls are of 1 to about 4 carbons, and may be branched or linear. Examples of lower alkyl include butyl, propyl, isopropyl, ethyl, and methyl. Likewise, radicals using the terminology "lower" refer to radicals preferably with 1 to about 4 carbons in the alkyl portion of the radical. [0027] As used herein, "amido" means a H-CON- or alkyl-CON-, carbocyclyl-CON-, aryl-CON-, heteroaryl-CON- or heterocyclyl-CON group wherein the alkyl, carbocyclyl, heteroaryl, aryl or heterocyclyl group is as herein described. [0028] As used herein, "aryl" means an aromatic radical having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) with only carbon atoms present in the ring backbone. Aryl groups can either be unsubstituted or substituted with one or more substituents, e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, 9 WO 2013/151708 PCT/US2013/031055 alkoxy, nitro, halo, mercapto, and other substituents. A preferred carbocyclic aryl is phenyl. 100291 As used herein, the term "heteroaryl" means an aromatic radical having one or more heteroatom(s) (e.g., N, 0, or S) in the ring backbone and may include a single ring (e.g., pyridine) or multiple condensed rings (e.g., quinoline). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents, e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-djpyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3 c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, and others. [00301 In these definitions it is clearly contemplated that substitution on the aryl and heteroaryl rings is within the scope of certain embodiments. Where substitution occurs, the radical is called substituted aryl or substituted heteroaryl. Preferably one to three and more preferably one or two substituents occur on the aryl ring. Though many substituents will be useful, preferred substituents include those commonly found in aryl compounds, such as alkyl, carbocyclyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like. 10031] As used herein, "amide" includes both RNR'CO- and RCONR'-. R can be substitutented or unsubstituted alkyl, substitutented or unsubstituted heterocyclyl, substitutented or unsubstituted heteroaryl, substitutented or unsubstituted aryl, or substitutented or unsubstituted carbocyclyl. R' can be H or substitutented or unsubstituted alkyl. 10032] As used herein, "halo", "halide" or "halogen" is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. Most preferred halide is fluorine. 10 WO 2013/151708 PCT/US2013/031055 [0033] As used herein, "haloalkyl" means a hydrocarbon substituent, which is a linear or branched or cyclic alkyl, alkenyl or alkynyl substituted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbons in length, more preferred haloalkyls are 1 to about 2 carbons, and most preferred are 1 carbon in length. The skilled artisan will recognize then that as used herein, "haloalkylene" means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group. [0034] As used herein, "heterocyclyl" means a cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Heterocyclyls may be substituted or unsubstituted with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, and other substituents, and are attached to other groups via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one up to three of 0, N or S, and wherein when the heterocycle is five membered, preferably it has one or two heteroatoms selected from 0, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-bipyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others. [0035] As used herein, "substituted amino" means an amino radical which is substituted by one or two alkyl, carbocycyl, aryl, heteroaryl or heterocyclyl groups, wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above. 11 WO 2013/151708 PCT/US2013/031055 [00361 As used herein, "substituted thiol" means RS- group wherein R is an alkyl, an aryl, heteroaryl or a heterocyclyl group, wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above. 100371 As used herein, "sulfonyl" means an alkylSO 2 , arylSO2, heteroarylSO2, carbocyclylSO2, or heterocyclyl-S02 group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above. [00381 As used herein, "sulfonamido" means an alkyl-S(O) 2 N-, aryl-S(0)2N-, heteroaryl-S(O)2N-, carbocyclyl-S(0)2N- or heterocyclyl-S(O)2N- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described. [00391 As used herein, when two groups are indicated to be "linked" or "bonded" to form a "ring," it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions, and it is within the purview of the skilled artisan to both envision such rings and the methods of their formations. Preferred are rings having from 3-7 members, more preferably 5 or 6 members. As used herein the term "ring" or "rings" when formed by the combination of two radicals refers to heterocyclic, carbocyclic, aryl, or heteroaryl rings. 100401 The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures are only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this invention, though such resonance forms or tautomers are not represented herein. [00411 The compounds provided herein may encompass various stereochemical forms. The compounds also encompasses diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed 12 WO 2013/151708 PCT/US2013/031055 compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. [00421 The term "administration" or "administering" refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease. [00431 A "diagnostic" as used herein is a compound, method, system, or device that assists in the identification and characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art. 100441 The term "mammal" is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species. [0045] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active 13 WO 2013/151708 PCT/US2013/031055 ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies. [0046] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297. [00471 "Solvate" refers to the compound formed by the interaction of a solvent and a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates. 14 WO 2013/151708 PCT/US2013/031055 [00481 "Patient" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. 100491 By "therapeutically effective amount" or "pharmaceutically effective amount" of a compound as provided herein is one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. "Therapeutically effective amount" is also intended to include one or more of the compounds of Formula (I) in combination with one or more other agents that are effective to inhibit Wnt related diseases and/or conditions. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou, Cancer Research (2010), 70(2), 440-446, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient's height, weight, sex, age and medical history. [00501 A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and includes curing a disease. "Curing" means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage). [00511 "Treat," "treatment," or "treating," as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder and/or reducing the severity of symptoms that will or are expected to develop. 15 WO 2013/151708 PCT/US2013/031055 [00521 "Drug-eluting" and or controlled release as used herein refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body tissue. [0053] "Drug-eluting material" and or controlled release material as used herein refers to any natural, synthetic or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time. [0054] "Elutable drug" as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body. Compounds [00551 The compounds and compositions described herein can be used as anti-proliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating diseases or disorders associated with aberrant Wnt signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes. Such compounds and compositions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis. [0056] Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drug thereof of Formula (I):
R
2 N NH R1 /N N H [0057] In some embodiments, R1 is -heteroarylR3R4. [0058] In some embodiments, R2 is selected from the group consisting of H, heteroarylR , -heterocyclylR6 and -arylR . 16 WO 2013/151708 PCT/US2013/031055 [00591 In some embodiments, R 3 is selected from the group consisting of H, 9 10 1 1 1 12 heterocyclylR 8 , -NHC(=O)R?, -NHSO 2 R", -NR"R" and -(C1.
6 alkyl)NR" R. [00601 In some embodiments, there is the proviso that R 2 and RW are not both H. [00611 In some embodiments, R4 is 1-3 substituents each selected from the group consisting of H, C1.
9 alkyl, halide, -CF 3 , -CN, OR 13 and amino. [00621 In some embodiments, each R5 is independently 1-4 substituents each selected from the group consisting of H, C1.9 alkyl, halide, -CF 3 , -CN, OR' 3 , -C(=0)R 1 , 11 12 amino and -(C1.
6 alkyl)NR" R. [0063] In some embodiments, each R 6 is independently 1-5 substituents each selected from the group consisting of H, C1.
9 alkyl, halide, -CF 3 , -CN, OR 3 and amino. [00641 In some embodiments, each R 7 is independently 1-5 substituents each selected from the group consisting of H, C1.
9 alkyl, halide, -CF 3 , -CN, OR , amino, -(C 1 . 6 alkyl)NHSO 2 R", -NR 12 (C1- 6 alkyl)NR"R 12 and -(C 1
.
6 alkyl)NR'I
R
12. [00651 In some embodiments, R8 is 1-5 substituents each selected from the group consisting of H, C1.
9 alkyl, halide, -CF 3 , -CN, OR1 3 and amino. [0066] In some embodiments, R 9 is selected from the group consisting of C 1
.
9 alkyl, -heteroarylR 5 , -heterocyclylR6, -arylR 7 and -CH 2 carbocyclyl. 100671 In some embodiments, R1 0 is selected from the group consisting of C1.
9 alkyl, -heteroarylR, -heterocyclylR6, -arylR 7 , and -carbocyclylR 4 . [0068] In some embodiments, each R" is independently selected from C 1
.
6 alkyl. [0069] In some embodiments, each R1 2 is independently selected from the group consisting of H and C1.
6 alkyl. [00701 In some embodiments, each R" and R are optionally linked to form a five or six membered heterocyclyl ring. [0071] In some embodiments, each R1 3 is independently selected from the group consisting of H and C1.
6 alkyl. [00721 In some embodiments, R 1 4 is 1-5 substituents each selected from the group consisting of H, C1.
9 alkyl, halide, -CF 3 , -CN, OR1 3 and amino. 17 WO 2013/151708 PCT/US2013/031055 [00731 In some embodiments, there is the proviso that Formula I is not a structure selected from the group consisting of: O NN N- NH N N N NH O NH 0 NH N 0 N N N H N H N H N H H H N NH N NHN NH N H NN N NN ~ N/ H H H H N N /H OXNH CNH0"N 1JH N. NH 0 N NH ~ NH nN N N /- NH-\ NH /' NH \H H H~ NHN NNN N ,NN NN N N N [H In He o nH H il 0 / N . N . N NH NH NHNHN N N N N \N N N ,N N N /N I NI H InH smH e dH N N N N/ \/ N 0N NHIs em bdmn NH NH NHN N H N H \NN 18, IN N /~N- N an H ,H ,H H H n N '- NHN N N H [0074] In some embodiments, R' is pyridineR 3
R
4 . [0075] In some embodiments, R' is pyridin-3-yR 3
R
4 . [00761 In some embodiments, R3 is H. 11 12 [00771 In some embodiments, R3? is -(C 1
-
6 alkyl)NR R [0078] In some embodiments, W 3 is -(C 1
-
4 alkyl)NR"R 2 [0079] In some embodiments, RW is -(C 1
-
2 alkyl)NR 11 R' [00801 In some embodiments, R3 is -CH 2
NR
1
R
1 [00811 In some embodiments, R 3 is -NR"R 2 18 WO 2013/151708 PCT/US2013/031055 [00821 In some embodiments, R 1 is -(C 1 2 alkyl). [00831 In some embodiments, R1 2 is -(C 1 2 alkyl). [00841 In some embodiments, R1 2 is H. [0085] In some embodiments, R 4 is H. [00861 In some embodiments, R 4 is amino. [00871 In some embodiments, R1 and R 12 are linked to form a five or six membered heterocyclyl ring. [0088] In some embodiments, R" and R 12 are linked to form a morpholine ring. [00891 In some embodiments, R 1 and R1 2 are linked to form a piperidine ring. [00901 In some embodiments, R" and R 12 are linked to form a pyrrolidine ring. [0091] In some embodiments, R" and R 12 are linked to form a piperazine ring. [00921 In some embodiments, R 1 ' and R1 2 are linked to form N [00931 In some embodiments, R3 is -NHC(=O)R 9 . [00941 In some embodiments, R 9 is -(C 2
-
5 alkyl). [0095] In some embodiments, R9 is phenyl. [0096] In some embodiments, R9 is -CH 2 carbocyclyl. [00971 In some embodiments, R 3 is -NHSO 2 R'0. [00981 In some embodiments, R 10 is -(C 1 4 alkyl). [0099] In some embodiments, R 10 is phenyl. [00100] In some embodiments, R3 is -heterocyclylR . [00101] In some embodiments, R3 is morpholine. [001021 In some embodiments, R3 is piperazine. [001031 In some embodiments, RW is piperidine [00104] In some embodiments, R3 is 1-methylpiperazine. [001051 In some embodiments, R 2 is -heteroarylR 5 . [001061 In some embodiments, R2 is -pyridinylR. [00107] In some embodiments, R2 is -pyridin-2-ylR 5 . 19 WO 2013/151708 PCT/US2013/031055 [001081 In some embodiments, R2 is -pyridin-3-ylR 5 . [001091 In some embodiments, R2 is -pyridin-4-ylR. [001101 In some embodiments, R5 is 1-2 fluorine atoms. [001111 In some embodiments, R2 is thiopheneR 5 . [00112] In some embodiments, R2 is furanR. [001131 In some embodiments, R 2 is imidazoleR 5 . [001141 In some embodiments, R 2 is selected from the group consisting of: 0
SSS
K F O K ,and N iN [001151 In some embodiments, R2 is -heterocyclylIR6. [001161 In some embodiments, R2 is morpholine. [00117] In some embodiments, R is piperazine. [00118] In some embodiments, R is piperidine 1001191 In some embodiments, R2 is 1-methylpiperazine. [001201 In some embodiments, R 6 is selected from the group consisting of H, F and -(C 1
.
4 alkyl). [00121] In some embodiments, R2 is -arylR 7 . [001221 In some embodiments, P2 is -phenylR 7 . [001231 In some embodiments, R7 is 1-2 fluorine atoms. [001241 In some embodiments, R7 is -(C 1
-
6 alkyl)NHSO 2 R". [00125] In some embodiments, R 7 is -(C 1 4 alkyl)NHSO 2
R"
1 . [00126] In some embodiments, R 7 is -(C 1 2 alkyl)NHSO 2 R". [001271 In some embodiments, R7 is -CH 2
NHSO
2 R". [00128] In some embodiments, R7 is -CH 2
NHSO
2
CH
3 . [00129] In some embodiments, R7 is -NR 12
(C
1 6 alkyl)NR" 1
R
12 . [001301 In some embodiments, R 7 is -NR 12
(C
1 4 alkyl)NR"R1. [001311 In some embodiments, R is -NR 2
CH
2
CH
2 NR R1. [00132] In some embodiments, R7 is -NHCH 2
CH
2 NR"R. [00133] In some embodiments, R7 is -NHCH 2
CH
2
N(CH
3
)
2 . 20 WO 2013/151708 PCT/US2013/031055 [001341 In some embodiments, R 7 is 2 substituents consisting of 1 fluorine atom and -NR 12 (C1.
6 alkyl)NR" R 1 2 . 1001351 In some embodiments, R 7 is 2 substituents consisting of 1 fluorine atom and -NHCH 2
CH
2
NR"R
1 . [001361 In some embodiments, R 7 is 2 substituents consisting of 1 fluorine atom and -(C 1
.
6 alkyl)NHSO 2 R". [001371 In some embodiments, R 7 is 2 substituents consisting of 1 fluorine atom and -CH 2
NHSO
2 R"l. [001381 In some embodiments, R 1 is pyridin-3-y1R 3 R4; R3 is H; R is H; R2 is selected from the group consisting of pyridine and -heterocyclylR 6 ; and R 6 is selected from the group consisting of H, F and -(C 1
.
4 alkyl). [00139] In some embodiments, R 1 is pyridin-3-ylR 3 R4; R is H; R is amino; R2 is selected from the group consisting of -heteroarylR 5 , -phenylR 7 and -heterocyclylR6. R is H; R6 is selected from the group consisting of H, F and -(C 1 4 alkyl); R7 is 1-2 fluorine atoms; and the heteroaryl is selected from the group consisting of pyridine, furan and thiophene. [00140] In some embodiments, R 1 is pyridin-3-ylR 3
R
4 ; R 3 is -NHC(=0)R; R 4 is H; R 9 is selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl; R2 is selected from the group consisting of H, -heteroarylR 5 , -phenyR 7 and -heterocyclylR6; R5 is H or F; R 6 is selected from the group consisting of H, F and -(C 1 4 alkyl); R7 is selected from the group consisting of 1-2 fluorine atoms and -CH 2
NHSO
2
R
11 ; and the heteroaryl is selected from the group consisting of pyridine, furan and thiophene. [00141] In some embodiments, R' is pyridin-3-ylR R4; R is -CH 2 NRR 1; R is H; R2 is selected from the group consisting of H, -heteroarylR 5 , -phenylR 7 and heterocyclylR 6; R is selected from the group consisting of H, F, Me and -C(=O)Me; R6 is selected from the group consisting of H, F and -(C 1
.
4 alkyl); R7 is 1-2 fluorine atoms; R" and R are linked to form a five-membered heterocyclyl ring; the heterocyclyl ring is substituted with 1-2 fluorine atoms; and the heteroaryl is selected from the group consisting of pyridine, furan and thiophene. [00142] Illustrative compounds of Formula (I) are shown in Table 1. 21 WO 2013/151708 PCT/US2013/031055 Table 1. N/ NN N/N NH 0 NH N H N N N 2 N NH \NH \N H N y N N- N HH H NN/N 4 N 4\NH 5 NNH 6 NNH ~ ,N N N a N N N1 H - H H N F N N NN N 7 N\NH 8 0 NH 9. NNH N N~ NH N N N N N N NN H~ N N HH F H FF N/N F/ N 10 0 NHN \ H 1 0 1NN \ N H 2 0 NH N \NH IN Nx N /N N N - N H H F F F F F/\/ N N/N 0 NH -~0 NH 13 N 14 N15N I \NH N NH N\H N N N N, /NN NN /N H H H 22 WO 2013/151708 PCT/US2013/031055 F F NN 18NHN 16 17N 18 N N N NH N N -N N N~ N/~ H H F FF F 00 N /N XNNHe 0- 0 N NH 19 N NH 20 N 21 N \ NH NHN N N- ~ Nx ~ N - N -s N N H H F F N ~ NN 2 2 0 N H F N - 0H 2 O N N NH 4 0 N H N N NX NX 'N \ N -N HH - N H F6F F 25 /NNN 2 NHN 26 0 HN 27 N INH I \ NH 11 \ NH NN N -~ N N / N/ H H H F 0 NH N NH N0 NHN N 28 N \NH 29 N \NH 30 N\NH NN N- / N N /N N M N ___H HH 23 WO 2013/151708 PCT/US2013/031055 F F F N 32 33N NNH NHH NH.\ 31 1NH 3N NH 3N\\N N N /N /N >N >N >N H H IH F FF /NN O4 NH 35. 0 NH 36 NH N 34NN N 36\H N / I N N > NNN H HH N/ / F/\ / o NH -~0 NH - ~ 0 NH 37 N\NH 38 N\NH 39 N N N N > N > N > N/ H H H F N "~/* N ~ NN o NH -. 0 NH N 41 N 40 N\NH 4N\ NH 42 N\\N N > /N N/NNN > N H NN N H H HO/ O N N /N N 43 N NH 44 N NH 45 N N NN / N N N N >N H H H. 24 WO 2013/151708 PCT/US2013/031055 F F F N N 46 N4N N\N 48 N ~N N ~ N N N N ~ N H H H F OH F N /N N/N NN ~N
.
N 49 N N\\ H 50 CNN\ H 51 N NH 1 11 NN ~ N /N HN N HN N/N N /N N /N V\N NN N N N 52 ~ -\H 53H H 5 -\N / ~ N N/ N N N N -P ' NP 5\\H 5H 5H HO HN HOH N/N /N N~ NNW~ 5NH N N H N-) N- N N _ N N Z/ N N N~N 5NH 5H 5H /N / N HO H N N N 58N\H N N\N H H HO HO N Oo HON ON IN N N/ 58NNH N NH 601 NH N N /N N N N/ NN H H H 0 HO HO2H WO 2013/151708 PCT/US2013/031055 o HN/- H/ N/N 0 HN N/ N H NH NH N N N /N /N / ~ NN N H H H N N N -~ /N 67 - NH F 68 NH F 69 , NH F NN \NH N \N H\NH > N N "'N N ' 0N 0N 0- N. N N H I H N N H H H /N /NN 76 NH F 71 NH F 72 ' NH F N Nx N Nx N/ N HN H N 26N WO 2013/151708 PCT/US2013/031055 HO -- HO - HO - N N N 0N N N \NH \N \NH F8 N 79 N/ Ni NHN N NN N~ -N - N H H H FF F N N 8 2N H 2 8 3N 4 82\ NH 83\ NH 84 NH N Nx Ny - N N H N H HH N N O5 0 NH 86. 0 NH N 0 8 NH N N N N 85N 86 NN \,N NH87HN N NN NX N N~ NN H __N H H NH \\ NH \\ .
0H NH\ N N 89 NN9 N N N /N N / __H H H F F27 WO 2013/151708 PCT/US2013/031055 N NN 0 NH HN /N HN 94 N \5NH 9 I\ H I - 96 1 \NH N Nx - NX N ~ N - N/ - N H H H F/ /N F/ /N N N N 97 N- \NH 98 N- \NH 99 N\NH N ~ N NA H H H F/FN F HN J N -. 0 NH 100 '.\NH 101 N\NH 102 \NH N N NN Z H H H F/ NF /\ /N /HN NH NH N 0 NH N - N N H H H F / /NF/\/ F/ N NN N ND N 106 1 N H 107 \NNH 108 N\NH N~ Ny NX -N N N ~ N N N H H H F ,N F N FH 0 NH 0 0H NH N N 10 NHN/N N H N HH H 28 WO 2013/151708 PCT/US2013/031055 /NN H / O NH 0 NH H 112 N \ 1NH 3 N 114 Z NH NH N\NH N N- N ~ -N N ~ N H FH H F NF HN
NIH
2 115 N\NH 116 N\NH 117 - \NH N N N X No-~ -N XN N~ N H H H F F F HN N /N 118 N~ NH 19 H NI\ NH 120 N~ NNH N NX Nx -N /~ N /~ N H H H F FIF NHNH -. 0 NH 121 N N \NH 122 N \NH 123 N NH N / N /~ N/ H H H F .F F N /NN ',NH'I D 124 1 N \ NH 125 11\ NH 126 1 N \ NH NN N N- N N N'/ H H .. H F F F N N- > Ni~/ 0 NH -. 0 NH 127 N NNH 128 N \NH 129 1 N \ NH N NN NN N N - N / N N/N H H H 29 WO 2013/151708 PCT/US2013/031055 F FF 0 N H -N0 NH N0 NHN 130 1 \ NH 131 11NH 132 1N \ NH N ,NN N N / N H H H FF N FN HN HN NH,'I N 13N NH 134 N N 135 \ NH N>/ N N- \N ~ N NN H H H /N N /N\ HN N 17NH N 136 \NH 17N 138 \NH N> N> N> - N N N / H H H N /N N " /N N Nl -- N N NNN 139 N \NH 140 N. \NH 141 N. NH N N - N > N N N H H H N N N N N NN - 0yN N N N > N N > N >N/ N / NN N 0/ H-N NN N N ~ N H H H /N\3 N WO 2013/151708 PCT/US2013/031055 /NN HN HN 0 NH 148 N\NH N4 150 N NH 149H NH 11 N N N N N N - N /~ N /~ N H H H 7 N N 0 NH - ~ NH 2 151 NH 152 N\NH \53NH N Ny No - N N N / H HH NN N N N~/H N N N~N 154 -\NH 155 \'-- NNH 156 -\NH N N -' N ~ N/NN/N H H H O NH - ~ 0NH NP : N\ / 157 N \NH 158 N N\NH 159 NC~N H-IH H / N N/ NH - N o NH N -' N -~ N H~ H H HH NN N N NH NH N H 1 6 4N - . N H 16 NXH16 N~ NH 12x1N N N~ N H H H H3 WO 2013/151708 PCT/US2013/031055 N7 N 7 NH 0 NH NNO~N o N 166 N\H 167 N\NH 168 \NH ,N N N N \NN H H oH NH0 NH0 N N N N 169 N\NH 170 N\NH 171 N \ NH N> N> N> N ,N N >N / N N N H H H HN HN 0 NH NP 12N 13 6N 174 \NH 172 NH 17 NH N N~ ,N> >N >N H H H /N N/ NHN 0 H NH 2 N 175 N\NH 176 N\ NH 177 NH N NN N H H HH HH N N N NN N 178 N\NH 179 11N\NH 180 N\NH N N N N N N N N H H H /NN 181 0N N \\ NH 182 :NH N \NH 183 N NH N N >N >N H H H 32 WO 2013/151708 PCT/US2013/031055 N /N / /N N N ,NH C o NH NN 184 N NH 185 NNH 186 \NH N '> N> \N /N NN N N - N H H H N /N/ N /N /N N N NH 187 N \NH 188 N \NH 189 N \NH N N N N~ N H - -H H /N o NH - 0 H NH 190 \NH 191 N NH N NNH N> H N> N~ / N~ N N N N H H H N /N /N N ~ -/N /N o NH -. 0 NH 0 NH 193 N\NH 194 N\NH 195 11NNH N N N N N N /N N/ N / N N/N N /N HNHN0 NH 16 HNH 197 HN \NH 198 11\ NH N> 11> ~ ' N> N N / N'/ NN H -N N / NH N NN N / N 09 NH NH2 0 H 2 1 \ N N N N,/ N N N N H HH 33 WO 2013/151708 PCT/US2013/031055 N/N NN CN/N CNHN NN N 202 N\NH 203 N\NH 204 N \NH ~~~ N~~N X N /~ N N~ N N H H H -P ON NH 0). CNH N/N 205 N 0 N 25NH 206 \NH 27NP 20 /- \NH '/ N N\ N N N N H H -H N/ N, N O NH NH 208 NC NH 209 N\NH 210 N\NH xN NN NN N/N N/ N N 0 NH 211 --- \NH 212 NH 23N N N- N~ Nx N N N N H H H 7N N CNN/N 0ONH O NH - ~ 0 NH -~N 214 N\N 215 N\N 216 \NH N-- N N /N /N NN -N xN H H H CN/N N/N CN/N O NH ---. 0 NH 0 NH 217 N- \NH 218 N\NH 21 - N- \NH N. NX NN N N /N - N ~N -~ N H H H 34 WO 2013/151708 PCT/US2013/031055 N/ N/N HN HNN 0 NH 220 N\NH 221 N\ NH 22NN N NX NX N - NN N N~ N H H H N N NN N N N N_ / N 0 NH -P NH, 223 N\NH 224 N\NH 225 N\NH N N N N~N N NN - N - N -~ N H H H NN / HN N N N N / N NN N N N N~ Ny N N~ NN -~ N ~ NN/ H H H NN N NNN N N NN N 229 NH 230 XNH231 NP \NH ~ \NH~- \NH N Nx N N N NN ,N - N /AN -~ N H H H. N/ N~N /N N ,N /N o NH NHN 232 \ NH233 ~ N\H 23IN\N NHN -~NN N3 NN / N 3 NN NH 234 N /N NH N N N NN - N /~N -~ N H H H H3 WO 2013/151708 PCT/US2013/031055 N~/N N~, N Y N N / O~NN 0 NH 0 NH 0 N NP 238 N \N'3 N 240 NH N>9 1 N> N>H NN N N NN- N/ > N N N HHH NH N ,N / 1T N N /N N NN /N o 0 NH 0/N NN 241 N H 242 NNH 243 N \N N> / N> N N>N N / NH N ~NN/ NP H H H W N /N N /N INN N HN HN 0 NH - N N 245 NP 246 -. NH N>4 245 NNH > 1 N N/N N /N N N N H H H N/ N NN N N 0NN 250 '-.\ H 25 - NH 22NN NN 24 H 24H 29N\H N NN N/N N/ N/N N N NNH 0 NH 253 NNH 254 \NH 255 N\NH NN> N> N> \ N \N N> N / N/ H H H HN 36 WO 2013/151708 PCT/US2013/031055 NN NN N N NN NN N NHN -N N~ N58 H H H NN N/ /N 0 NH-NH NH N // 0~N NP 25 - N N/ 20N\H 21N\H H N/N NN O~ ~ NH 6&0NH~.. 262N \N \N\N N N H N H / N/ _N /N HN_0/N 0 -NH 0 N 265 N\N 266 N \N 2674 N NN N ~ NN N N~ N H H H /N\-ZN /N /N NN NHN 268 \NH 266 \NH \NH NN / N /N \N HN ----- N N 0 NH N N N 271 \NH 272 \1NH 273 \NH N~ NC N H /-N N' __HH H H N______________ N_________________ 37 WO 2013/151708 PCT/US2013/031055 N /N ',NH 274 0 NH IN 27 NH 1 7 N NH NH NIA N ININI IN N N NI~ N H H HN N /N /N N IN INNN 277 \NH 278 1\ -NH 279 \NH IN IN IN /~ IN H H H /N N /N O NH -. 0 NH 0. NH NN NN NN 280\NH 8 \NH 282 INNIN P/ NNP/NN HH H HHN N 08 JNH24X NH 28 0 NH NN IN NIN \N /N H INH H HNHI OH NH N N IN N IN / N IXN/INI I N H H H s /N sy /N s,- N o H ? NH 2 o NH NH 289 IN\NH 290 N \NH 291 IN\NH IN/IN N / I H I N H H 38 WO 2013/151708 PCT/US2013/031055 s /N s /N S- /N HN N N N 292 \NH 293 \NH 29 NH N N /N N -~ZN H H H s /N S /N s /N N 0.. ~H 0 NH 295 \NH 296 \NH 297 -\NH N/ N ~ N NN N H HH s N s- /N S /N 'NH 29 NH N 29 0 NH N / N N 298 NH \NH N N- N N ~ N \N H H 5 7 /N s /N s Z 7N N N N N N 301 - NH 302 -- \NH 303 ~ -\NH N N N7 N \N /N - N - N -~ N H H H s /N
S
7 N~,'/ 0 NH - ~ 0 NH -. 0 NH 304 N\NH 305 N \NH 306 1N\NH N NN N N N /N N/ H H H N y / N N>N /N /N Ns / H N H H HH 39 WO 2013/151708 PCT/US2013/031055 HN0 HNNNN NN 310 HNN 311 N\N 312 \ NH N
N
I N N /N ~N N~ N SN /N H HH H /N 0 NH 07NH 2 07N0, / 313 NNH 314 N\NH 315 N NNH N N -~ N NH H H 0,7N 0,7N 0,7N HNN N -N N N N 316/NH 1 \NH 31/ NH , N - N -~ N H H H /ll N 0, /N 9 0 NH0 N N N\ NH/ NH 319 N \NH 320 N 2 N NN , N / N / /N H H N H 0, N 0, N 0, /, NH NP-N NP 0 NH -N \NHN 322 N\NH 323 9-\H 324\N 11 N x N N N N N'/ - N H H (N 0,7/N 0,7N > 0,7 0 NH 325 N\NH 326 N\NH 327 N NNH N N- N1 I N /N N~ /N /N H H N H 40 WO 2013/151708 PCT/US2013/031055 0y /N 0/N 0 N 0 ONH O NH 0 NH N N N30N\NH 328 NH 329 N NH 30N N N- N- \N.- N \N N/ - N -~ N H H H 0 /N 0 /N 0 /N NH - ~ 0 NH -~0 NH 331 ~ NH 332 \NH 33\N\ NH N N N \N /N N~ N -'N H H H F - EF / HN O /NHN Oy NN 334 N / 335 N 336 N N \NH \NH '- NH N \N ~ Ny N \N N SN HN H H FF FFF F FF N F/ N /N N N N 337 NH38NH 339 NNH N Ny Ny N \N /N /N - N ~ N -~ N H H H F F / F F /N F FN N\ NNN CN/N 3409 1 N\NH 34 N \NH 342 N\NH N N N N N - N /N N / H H H F F FEF FEF N 'ZN N N/NNN N N N 343 1 N N\NH 344 1 N NNH 345 N N\NH N N N N- N N N -N / N / H H H 41 WO 2013/151708 PCT/US2013/031055 NN NN NN 346\ N N\NH348 0 NF NH 346 \H37HNH N NN N\N NN H H -~ N H HNHN HN N N/ 349 0 NH F 350 HN F 351 F NP NH \NH \NH N N II\N N N -~ N H H H HN HN /- HN N N N \NH N NH \NH N ~ NN N N ~ N H H H HN HN HN 355 0 NH F ~j 356 0C NH F 357 0 NH F \NH \NHN N H H H HN HN H N N- N 358 0 NH F ~359 ',NH F -360 - F N N N N N HN H HH 42 WO 2013/151708 PCT/US2013/031055 H-N HN HN N N NH \NH \NH N ~N N N NW N ,N N j N H H H HN HN H N NN \NH N NH \NH NW . N~ N \N N N N N N HN H H HN HN-/HN HN N /N/ 367 0 NH \H 368 0NH F N369 0NH N \NHH F\HFNH N~ NN N W N / N/N/ H H H H WHN HN 015 370 HN F 371 HN F7 H NN 32 0 NF NH \NH \NH N N N / NH N H HH H H N / NN 373 0 NH F N 374 H2N F N N 375 FN N NN /N /N WN'N W N N N H H 43 WO 2013/151708 PCT/US2013/031055 H H H 00 0 N NHN 376 F NH 37 H 1 F NH 378 N'F N N NN N H H H N-/
N
7 N 0 / N NN 379 0 NH NH 380 N NH NH 381 0 NH N N \N N NH HH H H H H N 382 0 NH F N 383 INH F N N 384 FN F H N H NH ,N N N N Z ~ NN H HH H H H N-N
N
7 o 00 N N F N~0 H 385 F k 386 6F387 0 N N N /N N N N NN H HH H H H o 0 0 0 3 8 8 0 N H F N 8 0 N H F N 3 9 0 N H F N 38 0NH 38 N NH 39\1 NH N I N / N N / HN H H HH H H H 0 7 N N1 o'0 0 02NNHFN 0/H 391 0 NH F N. N 392 0 NH 39 0 l H. N H N N NN /N >N XN H H _ _H H 44 WO 2013/151708 PCT/US2013/031055 H H HN 00 N 0 NH SHN N N 34HN F F3N5-F 396 \N NH -\NH NN N > /-N>~ N ,N H N > N H H NN N s S NH 2 0 NH (S N/ N 397 N\ NH 398 \NH 399 jN NH N N N N H H HN HN S N ~ N N N H 0 400 \~NH 401\N 40\H NNNN N N N H H H \N ,N NH N H >NN N N \N N NH o NH H N NN 406~~~~ N\H47\N 0 N NN s N HN HS /" 0NH 6 N - N NH0 NH N 409 -~ NH 40N 11NN N> N N> N>N \ NN /N N H H S CINN o NH' 0 N N 41209N NH 4130N NH 414 1 \NH N > / N > N > N/N H H N> N > N 41 H H __ 45 WO 2013/151708 PCT/US2013/031055 N S S I 0 NH 0 NH ~ -0 NH 415/- 417 \15NH 41 \NH N \NH N NX N- N /N N I- N - N N I0 H H -H NF s HN SHN 0 NHN 418 HN N\N 419 N NN 420 N \NH ,N /N \ N H I NHN N& \N F /N / F / NHN 0 NH NH N F- NS NHF sN H N -NH 42 N H 42 NH H2H /N F /NN F s HN F s N 424 N \NH 425 N \NH 426 N \NH N ~N,- Nx N NN \N \N - N ~N /~ N/ NH H H F /N F NH N 0 NH F s, I \ o NHNq 427 N N\ NH 428 N N NH 429 0 N NH N, N~ N ~x ~N HN NN F N NI/N HNF o~~/ NHN NH1N NH 432 N\NH 430 N 431 N N ,- N NN N N' N /N H H H N F N F S F s N 0 N NNHN N3 N/ NH 434 N \ NH 435 - N N NH NN N N N ~ N NN/ H H H 46 WO 2013/151708 PCT/US2013/031055 / N N N)N s / F s F s C N o NH 0 NH N NN N/NN N N / N N /N H H H / N /N FF s F s o NH -. 0 NH ~ -0 NH N 40NP 441 N 439 \NH 44 \NH \NH N N N \NN /N N N N HN~~ F N N F s0 N NN 442 N\F 0~ \NNH N NP 444 NH 442 N H 43NHH N NH\ 2 oN NHNN s- NN, ~ N H- N H H /4 H 46N /N7 S N N N N /N /N 44 -\H 49H 40 '-H NN ,N s NN s N -s o4 NH 449/N NH 450 N\ NH N NN N 453/ NN 45NH 42H \H N - H N s N -~ N H HH 41 0NNH 45\ NH 456 NH~ N NH ,NN H~ H H HH ____ N__N_455___NH___N_ NH_456__N_\\_NH 47 WO 2013/151708 PCT/US2013/031055 IN /\N/ N s CN S s 0 NH NNH NP 457 - \NH 458 i\H 459 \NH \N N "N NN ~ NH X N H H 0 NH s- 0 NH sN0 NH N N N N 460 NNH 461 N\/ NH 462 \NH NN N\N N \ "N \N"' SN ~N H HH I N N N s s s O0 NH -. 0 NH -. 0 NH 43N NH 464 N 45N -'NN NH~.NX ' N N N N N N - N -~ N N H H H NN N HN N HN s 0 N 46N / 47N 468 N 466H 47'. NH '-. \NH N N SN N - N 0 H 0 H 0 H o6 H N NH 47 NH 2 N H 471 N N 46 NNN NNHNN ,N N ,N ~ N /"" N' / N/ H H H N~ N 472 N\\N 273 H N \NH 474 N N N N,/N N- / N7N N/N - N H H H 48 WO 2013/151708 PCT/US2013/031055 0 NH NH 0 NH 475 N\NHH 476 N \NH 47 N \NH ~ NX N7 N1 N ~ NI~, N H H 0 0 H- 0 N/N /N 0 NH " NH l 478J N7 N 480 N \ NH \NH \NH N ~ Ny
N~
N ~ N /~ H H H 0 H0 H0
/
7 /N N NN <DN 0N NH 484N8H 2 483 NP 482 N\H NH ~ NH N7 N N N~ N HN H H 0 .H0 s /N //N / 7 /N N~~N 484 0 H485 0 NH 486N N N N N NH \NH \NH N N/ N N/ NN N N7 N 47NN H 48NNH 8NH N\ H 0 NH NH N 0 NHN t01N N H47 H HH HN HN 490 HNN NH 491 HNN NH 492 N F N 1 NH \N N\ NH N N NN N N H H H 49 WO 2013/151708 PCT/US2013/031055 H 0 /6NN S N F s / N N 493 F 494 \ NH 495 N NH N HN N N NHN N/N N N N N -N H H F F N/? S N 496 N\NH 497N NN N N SN N H -~N H Administration and Pharmaceutical Compositions [001431 Some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of the indazole, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier. (001441 The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents. [00145] Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and other known agents are colorectal cancer, ovarian cancer, retinitis pigmentosa, macular degeneration, idiopathic pulmonary fibrosis and osteoarthritis. [001461 In some embodiments, colorectal cancer can be treated with a combination of a compound of either Formula (I) and one or more of the following drugs: 5-Fluorouracil (5-FU), which is often given with the vitamin-like drug leucovorin (also called folinic acid); Capecitabine (Xeloda*), Irinotecan (Camptosar*), Oxaliplatin (Eloxatin*). Examples of combinations of these drugs which could be further combined with a compound of either Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer, chemo 50 WO 2013/151708 PCT/US2013/031055 with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment). [001471 In some embodiments, ovarian cancer can be treated with a combination of a compound of either Formula (I) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (Doxil*), Gemcitabine (Gemzar*), Cyclophosphamide (Cytoxan*), Vinorelbine (Navelbine*), Ifosfamide (Ifex®), Etoposide (VP-16), Altretamine (Hexalen*), Capecitabine (Xeloda*), Irinotecan (CPT-11, Camptosar*), Melphalan, Pemetrexed (Alimta*) and Albumin bound paclitaxel (nab paclitaxel, Abraxane*). Examples of combinations of these drugs which could be further combined with a compound of either Formula (I) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin). [001481 In some embodiments, a compound of either Formula (I) can be used to treat cancer in combination with any of the following methods: (a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) Ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) and taxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposide and docetaxel; (g) Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i) Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate (Gleevec*, also known as STI-571), Gefitinib (Iressa, also known as ZD1839), Erlotinib (marketed as Tarceva®), Bortezomib (Velcade*) , tamoxifen, tofacitinib, crizotinib, Bel-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in clinical 51 WO 2013/151708 PCT/US2013/031055 trials), P13K inhibitors (eg. perifosine in a phase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD 0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MabThera* or Rituxan*), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as Erbitux*) and Bevacizumab (marketed as Avastin*); and (k) radiation therapy. [00149] In some embodiments, idiopathic pulmonary fibrosis can be treated with a combination of a compound of either Formula (I) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet*), prednisone, azathioprine, N-acetyleysteine, interferon-y 1b, bosentan (bosentan is currently being studied in patients with IPF, [The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal ofPharmacology (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids. [00150] In some embodiments, a compound of either Formula (I) can be used to treat idiopathic pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery. [00151] In some embodiments, a compound of either Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class. 100152] In some embodiments, macular degeneration can be treated with a combination of a compound of either Formula (I) and one or more of the following drugs: Bevacizumab (Avastin*), Ranibizumab (Lucentis*), Pegaptanib (Macugen), Aflibercept (Eylea*), verteporfin (Visudyne*) in combination with photodynamic therapy 52 WO 2013/151708 PCT/US2013/031055 (PDT) or with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc. [00153] In some embodiments, retinitis pigmentosa can be treated with a combination of a compound of either Formula (I) and one or more of the following drugs: UF-021 (OcusevaTM), vitamin A palmitate and pikachurin or with any of the following methods: (a) with the Argus* II retinal implant; and (b) with stem cell and/or gene therapy. [001541 Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracistemally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. Oral and parenteral administrations are customary in treating the indications. 1001551 Compounds provided herein intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g, tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. 53 WO 2013/151708 PCT/US2013/031055 Microwave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. [001561 The compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like. The term "excipient" is used herein to describe any ingredient other than the compound(s) provided herein. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, P, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non toxic carrier may be prepared. The contemplated compositions may contain 0.001% 100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 2 2 nd Edition (Pharmaceutical Press, London, UK. 2012). 54 WO 2013/151708 PCT/US2013/031055 [001571 In one preferred embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which the two active ingredients are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated. [001581 Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). [001591 In some embodiments, the unit dosage of compounds of Formula (I) is 0.25 mg/Kg to 50 mg/Kg in humans. [001601 In some embodiments, the unit dosage of compounds of Formula (I) is 0.25 mg/Kg to 20 mg/Kg in humans. [00161] In some embodiments, the unit dosage of compounds of Formula (I) is 0.50 mg/Kg to 19 mg/Kg in humans. [00162] In some embodiments, the unit dosage of compounds of Formula (I) is 0.75 mg/Kg to 18 mg/Kg in humans. [00163] In some embodiments, the unit dosage of compounds of Formula (I) is 1.0 mg/Kg to 17 mg/Kg in humans. 55 WO 2013/151708 PCT/US2013/031055 [00164] In some embodiments, the unit dosage of compounds of Formula (I) is 1.25 mg/Kg to 16 mg/Kg in humans. [00165] In some embodiments, the unit dosage of compounds of Formula (I) is 1.50 mg/Kg to 15 mg/Kg in humans. [001661 In some embodiments, the unit dosage of compounds of Formula (I) is 1.75 mg/Kg to 14 mg/Kg in humans. [00167] In some embodiments, the unit dosage of compounds of Formula (I) is 2.0 mg/Kg to 13 mg/Kg in humans. [001681 In some embodiments, the unit dosage of compounds of Formula (I) is 3.0 mg/Kg to 12 mg/Kg in humans. [001691 In some embodiments, the unit dosage of compounds of Formula (I) is 4.0 mg/Kg to 11 mg/Kg in humans. [001701 In some embodiments, the unit dosage of compounds of Formula (I) is 5.0 mg/Kg to 10 mg/Kg in humans. [00171] In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose. [001721 In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration of a precise dose. [00173] In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration of a precise dose. [001741 Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages. [00175] In some embodiments, the composition will comprise 0.1-10% of the active agent in solution. 56 WO 2013/151708 PCT/US2013/031055 [001761 In some embodiments, the composition will comprise 0.1-5% of the active agent in solution. 1001771 In some embodiments, the composition will comprise 0.1-4% of the active agent in solution. 1001781 In some embodiments, the composition will comprise 0.15-3% of the active agent in solution. [001791 In some embodiments, the composition will comprise 0.2-2% of the active agent in solution. [00180] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-96 hours. [00181] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-72 hours. [001821 In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-48 hours. [001831 In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-24 hours. [001841 In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-12 hours. [00185] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-6 hours. [00186] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m 2 to 300 mg/m 2 . [00187] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m 2 to 200 mg/m2. [00188] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m2 to 100 mg/m 2 . [00189] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 10 mg/m 2 to 50 mg/m 2 . [001901 In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 50 mg/m 2 to 200 mg/m2. 57 WO 2013/151708 PCT/US2013/031055 [001911 In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 75 mg/m 2 to 175 mg/m 2 . [001921 In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 100 mg/m 2 to 150 mg/m 2 . [001931 It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. [001941 In one preferred embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique. [001951 In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size is desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For optimal delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 pm are useful, with an aerodynamic particle size of about 1 to about 10 microns being preferred. Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles. 58 WO 2013/151708 PCT/US2013/031055 [001961 In some embodiments, compounds of Formula (I) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose* or the AERx* systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device. [00197] In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used. [001981 Alternatively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559). [001991 If desired, formulations of the invention can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211). [00200] In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea. [002011 Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments the acidic or basic solid compound of Formula I can be delivered from the reservoir of an external or internal implanted pumping system. 59 WO 2013/151708 PCT/US2013/031055 [00202] Formulations of the invention also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815). [00203] Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae. [002041 In some embodiments, the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like. [002051 Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted. [00206] Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition 60 WO 2013/151708 PCT/US2013/031055 is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent. [00207] Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In a preferred embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound. [002081 On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound. [002091 Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions. [00210] Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided herein, and directions for use of the kit (e.g., instructions for treating a patient). In another embodiment, the kit can include a compound or composition as described 61 WO 2013/151708 PCT/US2013/031055 herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Millierian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. Methods of Treatment [00211] The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can be treated with the 62 WO 2013/151708 PCT/US2013/031055 compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neurone disease, multiple sclerosis or autism, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome. [00212] With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer , pancreatic cancer and leukemias such as CML, CLL and T-ALL. The constitutive activation is due to constitutively active p-catenin, perhaps due to its stabilization by interacting factors or inhibition of the degradation pathway. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated. In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer. [002131 Other cancers can also be treated with the compounds and compositions described herein. [00214] More particularly, cancers that may be treated by the compound, compositions and methods described herein include, but are not limited to, the following: [002151 1) Breast cancers, including, for example ER breast cancer, ER breast cancer, her2- breast cancer, her2* breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal 63 WO 2013/151708 PCT/US2013/031055 carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER), progesterone receptor negative, and her2 negative (her2). In some embodiments, the breast cancer may have a high risk Oncotype score. [002161 2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma. [002171 3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma. [00218] 4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma. [002191 ) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma. 64 WO 2013/151708 PCT/US2013/031055 [002201 6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma. [002211 7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors. [00222] 8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma. [00223] 9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma. (002241 10) Hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstram's macroglobulinemia. 65 WO 2013/151708 PCT/US2013/031055 [00225] 11) Skin cancers and skin disorders, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma. [00226] 12) Adrenal gland cancers, including, for example, neuroblastoma. [002271 Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term "tumor cell," as provided herein, includes a cell afflicted by any one of the above identified disorders. [002281 A method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment. [002291 The compounds and compositions described herein can be used as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases. For example, the compounds described herein can inhibit the activity of one or more kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition. [002301 In addition, and including treatment of cancer, the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders. Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells. [002311 Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following: * a variety of cancers, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous 66 WO 2013/151708 PCT/US2013/031055 system and other tumors including melanoma, seminoma and Kaposi's sarcoma. e a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro-degenerative disorders such as Alzheimer's Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis. * defective apoptosis-associated conditions, such as cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, scleroderma, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and 67 WO 2013/151708 PCT/US2013/031055 reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteroporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Millerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome and Rett syndrome. [00232] Furthermore, the compounds and compositions described herein can be used to treat neurological conditions, disorders and/or diseases caused by dysfunction in the Wnt signaling pathway. Non-limiting examples of neurological conditions/disorders/diseases which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compression 68 WO 2013/151708 PCT/US2013/031055 neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barr6 syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, etachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neurone disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system 69 WO 2013/151708 PCT/US2013/031055 atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjogren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, 70 WO 2013/151708 PCT/US2013/031055 Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease and Zellweger syndrome. [002331 The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis. [002341 In some embodiments, the disclosure provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent. 1002351 In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [002361 In some embodiments, the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. 100237] In some embodiments, the disorder or disease is cancer. [002381 In some embodiments, the disorder or disease is diabetic retinopathy. [002391 In some embodiments, the disorder or disease is pulmonary fibrosis. [002401 In some embodiments, the disorder or disease is rheumatoid arthritis. [002411 In some embodiments, the disorder or disease is scleroderma. [00242] In some embodiments, the disorder or disease is a mycotic or viral infection. [00243] In some embodiments, the disorder or disease is a bone or cartilage disease. [00244] In some embodiments, the disorder or disease is Alzheimer's disease. [00245] In some embodiments, the disorder or disease is osteoarthritis. [00246] In some embodiments, the disorder or disease is lung disease [00247] In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative 71 WO 2013/151708 PCT/US2013/031055 vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Millierian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome. [002481 In some embodiments, the patient is a human. [002491 In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer. [002501 In some embodiments, the cancer is chosen from: lung cancer - non small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer - melanoma, small intestine cancer, stomach cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer. 100251] In some embodiments, the cancer is hepatocellular carcinoma. [00252] In some embodiments, the cancer is colon cancer. 1002531 In some embodiments, the cancer is breast cancer. [002541 In some embodiments, the cancer is pancreatic cancer. [002551 In some embodiments, the cancer is chronic mycloid leukemia (CML). 72 WO 2013/151708 PCT/US2013/031055 1002561 In some embodiments, the cancer is chronic myelomonocytic leukemia. [002571 In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). [002581 In some embodiments, the cancer is acute myeloid leukemia. 1002591 In some embodiments, the cancer is acute lymphocytic leukemia. [002601 In some embodiments, the cancer is Hodgkin lymphoma. [00261] In some embodiments, the cancer is lymphoma. [002621 In some embodiments, the cancer is sarcoma. [002631 In some embodiments, the cancer is ovarian cancer. 1002641 In some embodiments, the cancer is lung cancer - non-small cell. [002651 In some embodiments, the cancer is lung cancer - small cell. [002661 In some embodiments, the cancer is multiple myeloma. [002671 In some embodiments, the cancer is nasopharyngeal cancer. [00268] In some embodiments, the cancer is neuroblastoma. [002691 In some embodiments, the cancer is osteosarcoma. 1002701 In some embodiments, the cancer is penile cancer. [002711 In some embodiments, the cancer is pituitary tumors. [002721 In some embodiments, the cancer is prostate cancer. [002731 In some embodiments, the cancer is retinoblastoma. [00274] In some embodiments, the cancer is rhabdomyosarcoma. [00275] In some embodiments, the cancer is salivary gland cancer. [00276] In some embodiments, the cancer is skin cancer - basal and squamous cell. (002771 In some embodiments, the cancer is skin cancer - melanoma. [002781 In some embodiments, the cancer is small intestine cancer. [00279] In some embodiments, the cancer is stomach cancers. [002801 In some embodiments, the cancer is testicular cancer. [00281] In some embodiments, the cancer is thymus cancer. [002821 In some embodiments, the cancer is thyroid cancer. [002831 In some embodiments, the cancer is uterine sarcoma. 73 WO 2013/151708 PCT/US2013/031055 [002841 In some embodiments, the cancer is vaginal cancer. [002851 In some embodiments, the cancer is vulvar cancer. [002861 In some embodiments, the cancer is Wilms tumor. [002871 In some embodiments, the cancer is laryngeal or hypopharyngeal cancer. [002881 In some embodiments, the cancer is kidney cancer. 1002891 In some embodiments, the cancer is Kaposi sarcoma. [002901 In some embodiments, the cancer is gestational trophoblastic disease. [002911 In some embodiments, the cancer is gastrointestinal stromal tumor. [002921 In some embodiments, the cancer is gastrointestinal carcinoid tumor. [002931 In some embodiments, the cancer is gallbladder cancer. [002941 In some embodiments, the cancer is eye cancer (melanoma and lymphoma). [002951 In some embodiments, the cancer is Ewing tumor. [002961 In some embodiments, the cancer is esophagus cancer. [00297] In some embodiments, the cancer is endometrial cancer. [002981 In some embodiments, the cancer is colorectal cancer. 100299] In some embodiments, the cancer is cervical cancer. [003001 In some embodiments, the cancer is brain or spinal cord tumor. [003011 In some embodiments, the cancer is bone metastasis. [00302] In some embodiments, the cancer is bone cancer. [00303] In some embodiments, the cancer is bladder cancer. [00304] In some embodiments, the cancer is bile duct cancer. [00305] In some embodiments, the cancer is anal cancer. [00306] In some embodiments, the cancer is adrenal cortical cancer. [003071 In some embodiments, the disorder or disease is a neurological condition, disorder or disease, wherein the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, mutiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, 74 WO 2013/151708 PCT/US2013/031055 diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease. [003081 In some embodiments, the compound of Formula (I) inhibits one or more proteins in the Wnt pathway. 1003091 In some embodiments, the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins. [003101 In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT1OA, WNT1OB, WNTll, and WNT16. [00311] In some embodiments, the compound of Formula (I) inhibits a kinase activity. 1003121 In some embodiments, the method treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. [003131 In some embodiments, the compound of Formula (I) inhibits one or more Wnt proteins. [003141 In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. [003151 In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis. 1003161 In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. [003171 In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises 75 WO 2013/151708 PCT/US2013/031055 administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. [00318] In some embodiments, the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. [003191 In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 1003201 In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprises administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other agents. [003211 Moreover, the compounds and compositions, for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like. [00322] Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the GO. or G.
1 stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes. Evaluation of Biological Activity [003231 The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, e.g., WO 2001/053268 or WO 2005/009997. For example, the activity of a compound may be tested using one or more of the test methods outlined below. [003241 In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a compound (i.e. 76 WO 2013/151708 PCT/US2013/031055 inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above. [003251 In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of P-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of p-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt biological activity contacts a Wnt composition in the presence of a candidate inhibitor with cells, e.g. mouse L cells. The cells are cultured for a period of time sufficient to stabilize p-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for -catenin. [003261 In a further example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell (1997), 88(6), 747 756). [00327] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples. EXAMPLES Compound preparation [003281 The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The 77 WO 2013/151708 PCT/US2013/031055 skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds. [00329] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7 th Ed., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5 th Ed., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2 "d Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety)and the like. [00330] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety. [00331] Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention. [00332] 1H nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for 1H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, 78 WO 2013/151708 PCT/US2013/031055 triplet; q, quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; td, triplet of doublets; dt, doublet of triplets; m, multiplet. [00333] The following abbreviations have the indicated meanings: (Boc) 2 0 = di-tert-butyl dicarbonate brine = saturated aqueous sodium chloride CDCl 3 = deuterated chloroform CsCO 3 = cesium carbonate DCE = dichloroethane DCM = dichloromethane DEAD = diethyl azodicarboxylate DHP 3,4-dihydro-2H-pyran DMF = N,N-dimethylformamide DMSO-d 6 = deuterated dimethylsulfoxide ESIMS = electron spray mass spectrometry EtOAc = ethyl acetate Et 3 SiH triethylsilane HCl= hydrochloric acid HOAc = acetic acid KOAc = potassium acetate KOH = potassium hydroxide
K
3 PO4= potassium phosphate LAH = lithium aluminum hydride MeOH = methanol MgSO 4 magnesium sulfate NaBH 4 = sodium borohydride NaBH(OAc) 3 = sodium triacetoxy borohydride NaCNBH 3 = sodium cyanoborohydride Na 2
CO
3 = sodium carbonate NaHCO 3 = sodium bicarbonate NaHSO 3 = sodium bisulfite NaHSO 4 = sodium bisulfate 79 WO 2013/151708 PCT/US2013/031055 NaOAc = sodium acetate NMR = nuclear magnetic resonance ON = overnight PE = petroleum ether Pd/C = palladium on carbon Pd 2 (dba) 3 = tris(dibenzylideneacetone)dipalladium(O) Pd(dppf) 2 Cl 2 = 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride Pd(PPh 3
)
2 Cl 2 = dichloro-bis(triphenylphosphine)palladium (II) Pd(PPh 3
)
4 = tetrakis(triphenylphosphine)palladium(O) PPh 3 = triphenylphosphine PPTS = pyridinium p-toluenesulfonate rt = room temperature SEM 2-(trimethylsilyl)ethoxymethyl TEA triethylamine TFA = trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography [003341 The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application. Unless otherwise indicated, all variables are as defined above. 80 WO 2013/151708 PCT/US2013/031055 General procedures [003351 Compounds of Formula I of the present invention can be prepared as depicted in Scheme 1. H B B H H N N 0 B \N ~N R 1 -Br IV R!" -~N - N Suzuki N II III V
R
2 7 N VI
H
2 N/NH
NH
2 Cyclization
R
2 N R 2 )/ N NH N\ NH ,N N N NN Deprotection/ H N Vill vilob Scheme 1 [00336] Scheme 1 describes a method for preparation of indazole derivatives (VIII) by first reacting 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (II) with bis(pinacolato)diboron to form the borate ester (III). Suzuki coupling with various bromides (IV) yields indazole derivatives (V). Aldehyde (V) is reacted with various 1,2-diamines (VI) to produce (VII). Final deprotection of the pyrazole nitrogen yields the desired indazole derivatives (VIII). [003371 Alternatively, compounds of Formula I of the present invention can be prepared as depicted in Scheme 2. 81 WO 2013/151708 PCT/US2013/031055 0 H 0 0 H Br NaNO2, HC Br H SEM-Cl or Br r N Acetone, H 2 N H F p-TsOH, THF, NSEM or THP I H C-20 0 C, 3h XH 0 to r.t. h 80CXI B--B Pa(dppf)C 2 KOAc, DMF 110-C, 3 h
R
2 / N
)NR
2 N 0 H RNH H IV H IV B H R1 ~H 2 N" RB .7 NH 2 "N N 1 Br. N SEM or P-chloranil N SEM or Suzuki NSEM or THP MeCN THP THP XIV XIII XII 1. TFA, DCM
R
2 N 2. NH,, MeOH R\NH
R
1 ~ ~N H VIII Scheme 2 [00338] Scheme 2 describes an alternative method for preparation of indazole derivatives (VIII) by first formylating 5-bromo-1H-indole (IX) to produce 5-bromo-1H indazole-3-carbaldehyde (X) followed by protection with either SEM-Cl or DHP to give the protected aldehyde (XI). Aldehyde (XI) is then reacted with bis(pinacolato)diboron to form the borate ester (XII). Suzuki coupling with various bromides (IV) yields indazole derivatives (XIII). Aldehyde (XIII) is reacted with various 1,2-diamines (VI) to produce (XIV). Final deprotection of the pyrazole nitrogen yields the desired indazole derivatives (VIII). 82 WO 2013/151708 PCT/US2013/031055 Illustrative Compound Examples [003391 Preparation of intermediate (II) is depicted below in Scheme 3. 0/ N 0 0 C O O H OI ' 0 0 N NHOMe(Me)-HC NN N imidazole, DMF, 65"C N 12, DCM r.t. N H H H XV XVI XVII DHP, PPTS DCM, refluxed H N 0 N LAH o THF, C II XVIII Scheme 3 Step 1 1003401 IH-indazole-3-carboxylic acid (XV) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65'C for two hours and then allowed to cool to room temperature. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65'C for 3 hours. The reaction was concentrated to a paste and taken up in DCM, and washed subsequently with water and 2N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H indazole-3-carboxamide (XVI) as a white solid (100 g, 487 mmol, 79% yield). 'H NMR (DMSO-d 6 ) 6 ppm 3.46 (s, 3H), 3.69-3.85 (in, 3H), 7.13-7.31 (in, 1H), 7.41 (t, J=7.25 83 WO 2013/151708 PCT/US2013/031055 Hz, 1H), 7.56-7.65 (in, 1H), 7.93-8.08 (in, 1H); ESIMS found for CioH 1
N
3 0 2 m/z 206 (M+H). Step 2 [003411 To the N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVI) (20 g, 97.4 mmol) in DCM (1 L) was added bis(trifluoroacetoxy)iodobenzene (46 g, 107 mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at room temperature. After 1 hour, 600 mL of saturated NaHSO 3 was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with brine, dried over MgSO 4 , concentrated and the remaining solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVII) as a white solid (23.2 g, 70 mmol, 72% yield). 'H NMR (DMSO-d 6 ) 6 ppm 3.45 (s, 4H), 3.77 (s, 4H), 7.45-7.54 (in, 1H), 7.66 (dd, J=8.81, 1.51 Hz, 1H), 8.40 (d, J=1.01 Hz, 1H); ESIMS found for CioH 1 oIN 3 0 2 m/z 331 (M+H). Step 3 [003421 A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3 carboxamide (XVII) (16.5 g, 50 mmol), 3,4-dihydro-2H-pyran (10.3 mL, 113 mmol) and PPTS (0.12 g, 0.6 mmol) in DCM was heated to reflux for 5 hours. The solution was poured into a saturated NaHCO 3 solution, the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with 5% aqueous citric acid and brine, dried over MgSO4, and concentrated. The crude product was purified on a silica gel column (100% EtOAc -+ 3:97 MeOH:DCM) to provide 5 iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (XVIII) as a white viscous oil (19.1 g, 46 mmol, 92% yield). 1 H NMR (DMSO-d 6 ) 6 ppm 1.28-1.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5H), 5.86-6.08 (m, 1H), 7.45-7.87 (in, 2H), 8.39 (s, 1H); ESIMS found for CisHisIN 3 0 3 m/z 416 (M+H). 84 WO 2013/151708 PCT/US2013/031055 Step 4 100343] Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to a cooled (0 0 C) solution of 5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H pyran-2-yl)-1H-indazole-3-carboxamide (XVIII) (1.46 g, 3.5 mmol) in THF. Stirring was continued at 0 0 C until the reaction was completed, approximately 30 min. The reaction was quenched by the slow addition of EtOAc at 0 0 C, and the whole mixture was poured into 0.4 N NaHSO 4 . The organic layer was washed with brine, dried over MgSO 4 , concentrated, and purified on a silica gel column (100% EtOAc -+ 3:97 MeOH:DCM) to give 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (II) as a white solid (0.90 g, 3.15 mmol, 72% yield). 11H NMR (DMSO-d 6 ) 6 ppm 1.50 1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m, 1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.84 (d, J=6 Hz, 11), 8.50 (s, 1H), 10.13 (s, 1H); ESIMS found for C 13
H
13 1N 2 0 2 m/z 357 (M+H). [003441 Preparation of SEM protected intermediate (XX) is depicted below in Scheme 4. 0 0 H H Br NBr-- Br NaN 2 , H SEM-CI " ,N O N AcetoneH 2 0 N NaHDMF N H 0-20 0 C, 3 h H 0 to r.t. h Ix X XIX o H O\ -/0 o 0 Pd(dPPf)C1 2 KOAc, DMF 110 0 C, 3 h 0 0 H 'OB N SEM XX Scheme 4 85 WO 2013/151708 PCT/US2013/031055 Step 1 [00345] A solution of NaNO 2 (110.4 g, 1.6 mol, 8 eq) in water (200 mL) was added dropwise to a solution of 5-bromoindole (IX) (39.2 g, 0.2 mol, 1 eq) in acetone (1000 mL) stirred at -10-+0 0 C, while adding NaNO 2 the solution temperature was maintained below 20 0 C. An aqueous 2N HCl solution (480 mL) was added slowly to the solution with vigorously stirring while keeping the internal temperature between 0 and 20 0 C. The solution was further stirred at 20'C for 3 h after the addition. The solution was concentrated under reduced pressure to remove acetone while keeping the temperature below 35'C. The solid was collected by filtration and transferred to a flask. Cold (-10 C) DCM (200 mL) was added and stirred for 30 min at -5'C, the solids were filtered and dried under vacuum at 40'C to get 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g, 151 mmol, 76% yield) as a brown solid. ESIMS found for C 8
H
5 BrN 2 0 m/z 225 (M+H). Step 2 [003461 To a suspension of NaH (6.6 g, 166 mmol, 1.10 eq) in DMF (500 mL) was added a solution of 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g, 151 mmol, 1.00 eq) in DMF (50 mL) dropwise at 0C over a period of 30 min. The mixture was stirred at room temperature for 2 h, then SEM-Cl (26.4 g, 159 mmol, 1.08 eq) was added dropwise and the mixture was stirred at room temperature for another 3 h. Then the mixture was poured into an ice-water mixture (1000 mL) and extracted with EtOAc (300 mL x 3), the organic phases were combined, dried over Na 2
SO
4 , filtered and concentrated in vacuo, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc = 20:1-10:1) to afford 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H indazole-3-carbaldehyde (XIX) as a mixture of regioisomers (53.0 g, 151 mmol, 100% yield) as a yellow oil. ESIMS found for C 1 4
H
1 9 BrN 2 0 2 Si m/z 355 (M+H). Step 3 [003471 To a solution of the mixed 5-bromo-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-indazole-3-carbaldehyde (XIX) (53.0 g, 151 mmol, 1.0 eq), bis(pinacolato)diboron (38.0 g, 150 mmol, 1.0 eq) and KOAc (44.0 g, 450 mmol, 3.00 86 WO 2013/151708 PCT/US2013/031055 eq) in DMF (1000 mL) was added Pd(dppf)C1 2 (7.7 g, 10.5 mmol, 0.07 eq). The mixture was stirred at 90 0 C under nitrogen for 10 h. The mixture was filtered; the filtrate was poured onto water (1000 mL) and extracted with EtOAc (500 mL x 3). The combined organic phases were dried, filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography on silica gel (PE:EtOAc = 10:1-*1:1) to give the 5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H indazole-3-carbaldehyde (XX) as a mixture of regioisomers (42.9 g, 106 mmol, 71% yield) as a yellow oil. ESIMS found for C 2 0
H
3 1
BN
2 0 4 Si m/z 403 (M+H). [003481 Preparation of THP protected intermediate (XXI) is depicted below in Scheme 5. 0 H 0 0 H Br NaNO 2 , HCI Br N C Br N - N Acetone,H 2 00 / N p-TsOH, THF, N H -20"C, 3 h H 80 0 C Ix X xxI o Scheme 5 Step 1 (00349] Procedure can be found in Scheme 4, Step 1. Step 2 {00350] Procedure can be found in Scheme 3, Step 3. 5-Bromo-1-(tetrahydro 2H-pyran-2-yl)-3a,7a-dihydro-1H-indazole-3-carbaldehyde XXI was isolated as a white solid (16.4 g, 52.7 mmol, 39.6% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.57-1.65 (in, 2H), 1.72-1.83 (m, 1H), 2.02-2.11 (in, 2H), 2.33-2.44 (in 1H), 3.76-3.83 (in, 1H), 3.84-3.93 (in, 1H), 6.08 (dd, J=2.5Hz, 9Hz, 1H), 7.72 (dd, J=1.5Hz, J=8.5Hz, 1H), 7.92 (d, J=9Hz, 1H), 8.28 (d, J=2Hz, 1H), 10.17 (s, 1H); ESIMS found C 13
H
15 BrN 2 0 2 m/z 311.0 (M+H). 87 WO 2013/151708 PCT/US2013/031055 [003511 Preparation of intermediate N-(5-bromopyridin-3-yl)isobutyramide (XXIV) is depicted below in Scheme 6. H
H
2 NI Br 0 NBr + J CI Pyridine 0 2 B C0 0 C-r.t., 15 h N 0 N XXII XXIII XXIV Scheme 6 Step 1 [003521 3-Amino-5-bromo pyridine (XXII) (1 eq) was dissolved in DCM and cooled to 0 0 C before adding pyridine (2.2 eq) and isobutyryl chloride (XXIII) (1.1 eq). The reaction mixture was stirred at room temperature for 15 h until TLC showed the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford N-(5-bromopyridin-3 yl)isobutyramide (XXIV) as an off-white solid, (71% yield). 1 H NMR (CDCl 3 ) 6 ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 611); ESIMS found
C
9
H
1 1 BrN 2 O m/z 243.05(M+H). [003531 The following compounds were prepared in accordance with the procedure described in the above Scheme 6. H N Br N XXV 1003541 N-(5-Bromopyridin-3-yl)propionamide (XXV): Off white solid (92% yield). 111 NMR (DMSO-d 6 ) 6 ppm 1.09 (t, J=7.54 Hz, 3H), 2.36 (q, J=7.54 Hz, 211), 8.36 (m, 2H), 8.65 (d, J=2.07 Hz, 1H), 10.26 (s, 1H); ESIMS found C 8
H
9 BrN 2 O m/z 231 (M+H). H N Br XXVI 88 WO 2013/151708 PCT/US2013/031055 1003551 N-(5-Bromopyridin-3-yl)butyramide (XXVI): Yellow solid (2.1 g, 8.64 mmol, 88.8% yield). ESIMS found C 9 HujBrN 2 0 m/z 243 (M+H). H N Br N XXVII [003561 N-(5-Bromopyridin-3-yl)pentanamide (XXVII): Yellow solid (2.0 g, 7.78 mmol, 85.3% yield). ESIMS found Ci 0
H
13 BrN 2 O m/z 257 (M+H). H N Br o N XXVIII 1003571 N-(5-Bromopyridin-3-yl)-3-methylbutanamide (XXVIII): Off white solid, (67% yield), 'H NMR (CDCl 3 , 500 MHz) 6 ppm 8.55-8.42 (m, 3H), 7.62 (s, 1H), 2.31-2.18 (m, 3H), 1.02-1.01 (d, J= 6Hz, 6H); ESIMS found CioH 13 BrN 2 O m/z 258.80 (M+H). H N Br N XXIX [003581 N-(5-Bromopyridin-3-yl)-3,3-dimethylbutanamide (XXIX): Yellow solid (1.7 g, 6.27 mmol, 78.6% yield). ESIMS found CuIH 15 BrN 2 0 m/z 271 (M+H). H o N Br XXX [003591 N-(5-Bromopyridin-3-yl)pivalamide (XXX): Off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, IH), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found CioHj 3 BrN 2 0 m/z 257.0 (M+H). 89 WO 2013/151708 PCT/US2013/031055 H N Br [003601 N-(5-Bromopyridin-3-yl)-2-phenylacetamide (XXXI): White solid (2.5 g, 8.59 mmol, 77.9% yield). ESIMS found C13HBrN 2 0 m/z 291 (M+H). H N Br N XXXII [003611 N-(5-Bromopyridin-3-yl)benzamide (XXXII): White solid (2.7 g, 9.74 mmol, 60% yield). ESIMS found C 1 2
H
9 BrN 2 0 m/z 277 (M+H). H N Br XXXIII (00362] N-(5-Bromopyridin-3-yl)cyclopropanecarboxamide (XXXIII): Off white solid, (83% yield), oH NMR (CDCl3, 500 MHz) ppm 8.46-8.39 (m, 3H), 7.54 (bs, 1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMS found for
C
9
H
9 BrN 2 0 m/z 240.9 (M+H). H N Br 0 N XXXIV [00363] N-(5-Bromopyridin-3-yl)cyclobutanecarboxamide (XXXIV): Yellow solid (2.1 g, 6.27 mmol, 86.6% yield). ESIMS found CioH 11 BrN 2 0 m/z 255 (M+H). H N Br N XXXV 90 WO 2013/151708 PCT/US2013/031055 [003641 N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide (XXXV): Yellow solid (1.9 g, 7.06 mmol, 80.2% yield). ESIMS found CnIH 1 3 BrN 2 O m/z 269 (M+H). H N Br 0 N XXXVI [003651 N-(5-bromopyridin-3-yl)cyclohexanecarboxamide (XXXVI): Yellow solid (2.0 g, 7.06 mmol, 84.3% yield). ESIMS found C 12 Hi 5 BrN 2 O m/z 283 (M+H). H 0 N Br N N XXXVII [003661 N-(5-bromopyridin-3-yl)-l-methylpiperidine-4-carboxamide (XXXVII): Waxy brown solid, (43%, yield), 111 NMR (CDC1 3 , 500 MHz) 5 ppm 1.67 (dq, 2H), 1.77 (d, 2H), 1.96 (t, 2H), 2.20 (s, 3H), 2.31 (m, 111), 2.86 (d, 211), 8.36 (s, 1H), 8.40 (s, 111), 8.67 (s, 1H)m 10.34 (s, 111); ESIMS found C 12 Hi 6 BrN 3 O m/z 297.8 (MBr 79 +H) and 299.8 (MBr 8 1+H). H NBr N XXXVIII [00367] N-(5-bromopyridin-3-yl)methanesulfonamide (XXXVIII): Off-white solid, (67%, yield), 'H NMR (CDCl 3 , 500 MHz) 6 ppm 3.14 (s, 311), 7.80 (s, 111), 8.40 (s, 1H), 8,41 (s, 1H), 10.28 (brs, 1H); ESIMS found C 6
H
7 BrN 2 0 2 S m/z 250.9 (MBr 79 +H) and 252.9 (MB 88+H). Br N XXXIX 91 WO 2013/151708 PCT/US2013/031055 [003681 N-(5-bromopyridin-3-yl)benzenesulfonamide (XXXIX): White solid, (84%, yield), 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 7.58-7.61 (in, 2H), 7.65-7.67 (in, 2H), 7.83 (d, 2H), 8.15 (d, 1H), 8.38 (d, IH), 10.87 (brs, 1H); ESIMS found CnH 9 BrN 2 0 2 S m/z 314.3 (MBr81+H). 1003691 Preparation of intermediate (XLI) is depicted below in Scheme 7. r 0 Br Br o NH Br N
NC
3 ' Pd 2 (dba) 3 , xantphos N N CS0,Ab),N dioxane, MW, 100 0 C, 3h XL XLI Scheme 7 Step 1 [003701 To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in dioxane (14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO 3 (3.24 g, 9.93 mmol) and xantphos (123 mg, 0.21 mmol). The solution was degassed before adding Pd 2 (dba) 3 (195 mg, 0.21 mmol). The reaction was microwaved at 90'C for 4 h. The reaction was poured into a mixture of CHCl 3
/H
2 0; the aqueous layer was separated, washed with water, then brine and concentrated under vacuum. The crude product was purified on a silica gel column (100% hexane - 1:3 EtOAc:hexane) to give 4-(5-bromopyridin-3 yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6 mmol, 65% yield). ESIMS found
C
9 HuBrN 2 0 m/z 244 (M+H). [00371] The following compound was prepared in accordance with the procedure described in the above Scheme 7. N N XLII [003721 1-(5-bromopyridin-3-yl)-4-methylpiperazine (XLII): Brown oil (50%, yield), 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.21 (s, 3H), 2.41-2.43 (in, 4H), 3.22-3.24 (in, 4H), 7.51-7.52 (in, 1H), 8.02 (d, J=1.9Hz, 1H), 8.28 (d, J=2.6Hz, 1H); ESIMS found CioH 14 BrN 3 m/z 256 (M+H). 92 WO 2013/151708 PCT/US2013/031055 [00373] Preparation of intermediate 5-bromo-N,N-dimethylpyridin-3-amine (XLIII) is depicted below in Scheme 8. Br Br Br Me 2 N*HCI, K 2 C0 3 DMF, 200"C, overnight N NN XL XLIII Scheme 8 Step 1 [00374] To a solution of 3,5-dibromopyridine (XL) (2.37 g, 10.0 mmol) in dry DMF (20.0 mL) was added K 2 C0 3 (4.5 g, 33 mmol) and dimethylamino hydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at 200C in a sealed tube. The solution was cooled to room temperature and excess DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic phase was separated. The aqueous phase was washed with EtOAc and the combined organic phases were dried over MgSO 4 , and concentrated to afford 5-bromo-N,N-dimethylpyridin-3 amine (XLIII) as an off-white solid (1.78 g, 8.85 mmol, 88% yield). 'H NMR (DMSO d 6 , 500 MHz) 8 ppm 2.94 (s, 6H), 7.25 (t, J=2Hz, 1H), 7.91 (d, J=2Hz, 1H), 8.07 (d, J=2Hz, 1H); ESIMS found C 7
H
9 BrN 2 m/z 201.1 (M+H). [00375] Preparation of intermediate 5-bromo-N-isopropylpyridin-3-amine (XLIV) is depicted below in Scheme 9. 0 H
H
2 N ~ Br HOAc, NaCNBH 3 N Br N-2 MeOH N N XXII XLIV Scheme 9 Steps 1 [00376] To a solution of 5-bromopyridin-3-amine (XXII) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 pL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH 3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was 93 WO 2013/151708 PCT/US2013/031055 partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic layer was dried over MgSO 4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane -+ 90:10 hexane:EtOAc) to produce 5-bromo-N isopropylpyridin-3-amine (XLIV) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 'H NMR (DMSO-d,, 500 MHz) 6 ppm 1.12 (d, J=6.3Hz, 6H), 3.55-3.59 (in, 1H), 6.03 (d, J=7.9Hz, 1H), 7.05-7.06 (in, 1H), 7.75 (d, J=2Hz, 1H), 7.90 (d, J=2Hz, IH); ESIMS found CsHu 1 BrN 2 m/z 215 (M+H). [003771 Preparation of intermediate 1-(5-bromopyridin-3-yl)-N,N-dimethyl methanamine (XLVI) is depicted below in Scheme 10. N OHC Br Br Me 2 NH*HCI Br N NaBH(OAc) 3 TEA, DCE XLV XLVI Scheme 10 Step 1 [00378] To a solution of 5-bromonicotinaldehyde (XLV) (5.0 g, 26.9 mmol) in DCE (108 mL) was added dimethylamine-HCI (4.39 g, 53.8 mmol) and TEA (7.5 g, 53.8 mmol). The reaction was stirred at room temperature for 1 h. NaBH(OAc) 3 was added and the reaction was stirred overnight at room temperature. The reaction was diluted with DCM and sat. aq. NaHCO 3 . The organic layer was separated, washed with water, brine, dried and concentrated under vacuum to produce 1-(5-bromopyridin-3-yl)-N,N dimethylmethanamine (XLVI) as a brown liquid (5.36 g, 24.9 mmol, 92.6% yield). 1H NMR (CDCl 3 ) 6 ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=1.lHz, 1H), 8.59 (d, J=2.2Hz, 1H); ESIMS found CsH,,BrN 2 m/z 215 (MBr 79 +H) and 217 (MBr81+H). [00379] The following intermediates were prepared in accordance with the procedure described in the above Scheme 10. N Br N XLVII 94 WO 2013/151708 PCT/US2013/031055 [003801 3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (XLVII): Golden liquid (1.35 g, 97% yield). 'H NMR (DMSO-d 6 ) 1.68-1.71 (m, 411), 2.42-2.44 (m, 4H), 3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for CioH1 3 BrN 2 m/z 242 (M+H). F N Br N XLVIII [003811 3-Bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridine (XLVIII): Brown oil (6.4 g, 81% yield). ESIMS found for CoH,,BrF 2
N
2 m/z 277.0 (M+H). N Br N XLIX [003821 3-Bromo-5-(piperidin-1-ylmethyl)pyridine (XLIX): Brown liquid (13.1 g, 94% yield). 'H NMR (DMSO-d 6 ) 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H), 2.31 2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for C 1 H1 5 BrN 2 m/z 257 (M+H). Br H N L 100383] N-((5-Bromopyridin-3-yl)methyl)ethanamine (L): Golden liquid (1.29 g, 6.00 mmol, 60% yield). ESIMS found for CsH,,BrN 2 m/z 215 (M+H). Br N LI [00384] N-Benzyl-1-(5-bromopyridin-3-yl)methanamine (LI): Golden liquid (77 mg, 0.28 mmol, 25% yield). ESIMS found for C1 3 H1 3 BrN 2 m/z 277 (M+H). [003851 Preparation of intermediate tert-butyl (5-bromopyridin-3-yl)methyl (cyclopentylmethyl)carbamate (LVI) is depicted below in Scheme 11. 95 WO 2013/151708 PCT/US2013/031055 0 NH 0 OHC Br NaBH 4 HO Br 0 N Br N MeOH N PPha, DEAD / I THF, 0~ r. t. 0 N XLV LIl LIll
NH
2
NH
2 EtOH r Br Br N\4 CN)N H2N Br H (BC2 H H2N Boc N EtN jC ~ NaBH 3 (CN)N MeOH N LVI LV LIV Scheme 11 Step 1 100386] To a solution of 5-bromonicotinaldehyde (XLV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH 4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (LII) (1.8 g, 9.57 mmol, 90.0% yield) as a colorless oil. 1H NMR (CDC1 3 , 500 MHz) 6 ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C 6
H
6 BrNO m/z 188 (M+H). Step 2 [00387] To a stirred solution of (5-bromopyridin-3-yl)methanol (LII) (1.60 g, 8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh 3 (3.33 g, 12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g, 12.75 mmol, 1.5 eq) dropwise at 0 0 C under N 2 . Then the reaction mixture was stirred at room temperature for 6 h. The mixture was washed with saturated NaHCO 3 solution (15 mL), water (15 mL) and brine (15 mL) subsequently. The organic layers were dried over MgSO 4 , concentrated under reduced pressure, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc = 4:1) to give 2 -((5-bromopyridin-3-yl)methy1)isoindoline-1,3-dione (LIII) 96 WO 2013/151708 PCT/US2013/031055 (2.5 g, 7.88 mmol, 82.3% yield) as a white solid. ESIMS found for C 1 4
H
9 BrN 2 0 2 m/z 317 (M+H). Step 3 [003881 A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LIII) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in EtOH (20 mL) was heated at 70'C for 3 h. The mixture was filtered through a Celite* pad and the filtrate was concentrated in vacuo, the crude product was dissolved in 1N HCl solution (15 mL) and concentrated to dryness, then it was washed with acetone (10 mL x 3), the precipitate was collected by filtration, dried in vacuo to give (5-bromopyridin-3 yl)methanamine (LIV) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid. 1H NMR (D 2 0, 500 MHz) 6 ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2Hz, 1H), 8.91 (d, J=1.6Hz, IH). ESIMS found for C 6
H
7 BrN 2 m/z 187 (M+H). Step 4 [00389] A solution of (5-bromopyridin-3-yl)methanamine (LIV) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH 3 CN (1.98 g, 34.6 nimol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSO 4 and concentrated in vacuo to give 1-(5 bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LV) (1.23 g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C 12
H
1 7 BrN 2 m/z 269 (M+H). Step 5 [00390] To a solution of 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl) methanamine (LV) (1.00 g, 3.7 mmol, 1 eq) and TEA (0.93 g, 9.2 mmol, 2.5 eq) in DCM (20 mL) was added portionwise (Boc) 2 0 (0.85 g, 4.0 mmol, 1.1 eq) at 0"C, the reaction mixture was stirred at room temperature for 1 h. The mixture was washed with water (10 mL), brine (10 mL), the organic layer was separated, dried over MgSO 4 and concentrated 97 WO 2013/151708 PCT/US2013/031055 in vacuo to give tert-butyl (5-bromopyridin-3-yl)methyl (cyclopentylmethyl)carbamate (LVI) (1.25 g, 3.38 mmol, 91.9% yield) as a white solid. ESIMS found for C 17
H
25 BrN 2 02 m/z 369 (M+H). [003911 Preparation of intermediate (LX) is depicted below in Scheme 12.
NH
2 NH 2 NH 2 0 2 N 0 2 N Br (Ho)0B O 2 N N HOAc, NaOAc 1,4-Dioxane, Na 2
CO
3 , H20 Br 2 , 100"C, 28 h N Pd(PPh 3
)
2
C
2 , reflux., 15 h N N N LVII LVIII LIX MeOH, Pd/C-H 2 rt, 15 h
NH
2
H
2 N N N LX Scheme 12 Step 1 100392] A mixture of 3-nitropyridin-4-amine (LVII) (10 g, 71.94 mmol) and acetic acid (120 mL) was added to a sealed tube followed by addition of NaOAc (29.50g, 93.52mmol) and dropwise addition of bromine (4.7ml 359.7 mmol) under stirring. The sealed tube was heated at 1 00C for 28 h until TLC showed consumption of starting material. The reaction mixture was concentrated to obtain a solid which was dissolved in water, basified with NaHCO 3 and extracted with EtOAc. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (LVIII) as a yellow solid (12 g, 55 mmol, 77% yield). 'H NMR (DMSO-d 6 ) 6 ppm 9.19 ( s, 1H), 8.58 (s, 1H); ESIMS found for C 5
H
4 BrN 3 0 2 m/z 217, 219 (M+, M+2). 98 WO 2013/151708 PCT/US2013/031055 Step 2 [003931 A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na 2
CO
3 solution (78 ml) and 1,4 dioxane (150 mL) was degassed with argon thrice. Pd(PPh 3
)
2 Cl 2 (927 mg, 5 mmol%) was added to the reaction and the solution was refluxed for 15h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite* and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc - 2:98 MeOH:DCM) to give 5-nitro-3,3'-bipyridin-4-amine (LIX) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1 H NMR (CDCl 3 , 500 MHz,) 6 ppm 9.31 ( s, 1H), 8.80-8.79 (in, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (in, 1H),7.52-7.48 (in, 1H). ESIMS found CioH 8
N
4 0 2 m/z 216.95 (M+H). Step 3 [003941 To a solution of 5-nitro-3,3'-bipyridin-4-amine (LIX) (5 g, 23 mmol) in MeOH (20 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 15 h. The suspension was filtered through Celite* and the concentrated under vacuum to produce 3,3'-bipyridine-4,5-diamine (LX) as off white solid (3.3 g, 17.7 mmol, 76% yield). 'H NMR (DMSO-d6, 500 MHz,): 6 ppm 8.63-8.53 (in, 1H), 7.90-7.83 (in, IH), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-7.43 (in, 2H), 6.13 (bs, 2H), 5.31 (bs, 2H). ESIMS found CioHioN 4 m/z 187.10 (M+H). [00395] The following compounds were prepared in accordance with the procedure described in the above Scheme 12.
NH
2 N
H
2 N N LXI [00396] 3,4'-Bipyridine-4,5-diamine (LXI): Light tan solid, (84% yield). ESIMS found CioHioN 4 m/z 187.0 (M+H). 99 WO 2013/151708 PCT/US2013/031055 HNH
H
2 N NH N N LXII [003971 2,3'-Bipyridine-4',5'-diamine (LXII): Tan amorphous solid, (76% yield). ESIMS found CioHioN 4 m/z 187.0 (M+H).
NH
2
H
2 N F N LXIII [00398] 5-(3-Fluorophenyl)pyridine-3,4-diamine (LXIII): Off white solid, (76% yield), 'H NMR (CDCl 3 , 500 MHz) 6 ppm 4.72 (s, 2H), 5.07 (s, 2H), 7.17-7.23 (m, 3H), 7.44 (s, 1H), 7.48-7.52 (m, 1H), 7.68 (s, 1H); ESIMS found CnHioFN 3 m/z 204.1 (M+H).
NH
2 F
H
2 N N LXIV [003991 5-(4-Fluorophenyl)pyridine-3,4-diamine (LXIV): Light yellow solid, (97% yield). ESIMS found C, H, 0
FN
3 m/z 204.3 (M+H).
NH
2
H
2 N N/F N LXV [004001 5-(2-Fluorophenyl)pyridine-3,4-diamine (LXV): Light red solid, (44% yield). ESIMS found C, HioFN 3 m/z 204.4 (M+H).
NH
2 N
H
2 N NH2 F N 100 WO 2013/151708 PCT/US2013/031055 LXVI [004011 5'-Fluoro-3,3'-bipyridine-4,5-diamine (LXVI): Off white solid, (100% yield), 'H NMR (CDC 3 , 500 MHz) 6 ppm 4.78 (s, 2H), 5.28 (s, 2H), 7.46 (s, 1H), 7.70 (s, lH), 7.73-7.76 (m, lH), 8.44-8.45 (m, 1H), 8.56 (d, J=2.8Hz, 1H); ESIMS found CioH 9
FN
4 m/z 205 (M+H).
H
2 N H 1 N LXVII [00402] 5-(Furan-3-yl)pyridine-3,4-diamine (LXVII): Light pink solid, (68% yield). ESIMS found C 9
H
9
N
3 0 m/z 176.0 (M+H).
NH
2 S
H
2 N N LXVIII [00403] 5-(Thiophen-3-yl)pyridine-3,4-diamine (LXVIII): Light brown amorphous solid, (100% yield). ESIMS found C 9
H
9
N
3 S m/z 192.0 (M+H). NH2\
H
2 N S N LXIX [00404] 5-(thiophen-2-yl)pyridine-3,4-diamine (LXIX): White amorphous solid, (1.257 g, 6.57 mmol, 100% yield). ESIMS found C 9
H
9
N
3 S m/z 192.2 (M+H). [00405] Preparation of intermediate (LXXI) is depicted below in Scheme 13.
NH
2 NH 2 N
NH
2 N 0 2 N Br -N NH 0 2 N N MeOH, Pd/C-H2 H 2 N I N N 140 0 C N rt, 15 h N LVIII LXX LXXI Scheme 13 101 WO 2013/151708 PCT/US2013/031055 Step 1 [00406] A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (618 mg, 2.83 mmol) in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140 0 C overnight. The reaction was poured into an EtOAc/H 2 0 mixture; the organic layer was separated, dried over MgSO 4 and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl 3 -* 3:97 MeOH(7N NH 3 ):CHCl 3 ) to give 3-(4-methylpiperazin 1-yl)-5-nitropyridin-4-amine (LXX) as a yellow solid (382 mg, 1,61 mmol, 56.7% yield). 'H NMR (CDCl 3 , 500 MHz,) 6 ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (in, 4H), 5.96 (s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found CIOH1 5
N
5 0 2 m/z 238 (M+H). Step 2 [004071 To a solution of 3
-(
4 -methylpiperazin-1-yl)-5-nitropyridin-4-amine (LXX) (382 mg, 1.61 mmol) in MeOH (11 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite* and the concentrated under vacuum to produce 5 (4-methylpiperazin-1-yl)pyridine-3,4-diamine (LXXI) as purple solid (330 mg, 1.59 mmol, 99% yield). 'H NMR (DMSO-d6, 500 MHz,): 6 2.18 (s, 3H), 2.34-2.36 (in, 4H), 3.13-3.16 (in, 4H), 3.89 (s, 2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H); ESIMS found CioH1 7 Ns m/z 208 (M+H). [00408] The following compounds were prepared in accordance with the procedure described in the above Scheme 13.
NH
2 0
H
2 N N N LXXII [00409] 5-Morpholinopyridine-3,4-diamine (LXXII): 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 3.10 (t, 4H), 3.65 (t, 4H), 3.93 (brs, 2H), 5.23 (brs, 2H), 5.94 (s, 1H), 7.33 (s, 1H); ESIMS found C 9 H1 4
N
4 0 m/z 195 (M+H). 102 WO 2013/151708 PCT/US2013/031055
NH
2
H
2 N I N N LXXIII [00410] 5-(Piperidin-1-yl)pyridine-3,4-diamine (LXXIII): Purple solid, (83% yield). ESIMS found CioHi 6
N
4 m/z 193.1 (M+H). [004111 Preparation of intermediate (LXXVIII) is depicted below in Scheme 14. Br H HN O o HN 0 0 Br F tBuOK Br F KOAc, PdCI 2 (dppf) 2 0 -B X F toluene, 110 0 C DMIF, 95"C, 2 h LXXIV LXXV LXXVI
NH
2 0 2 N Br LVIII N
K
3 P0 4 , Pd(PPh 3
)
4 HN HN H 2 0, 100"C, 3 h
NH
2
NH
2
H
2 N ~F 10% Pd/C-H 2
O
2 N F N MeOH N LXXVIII LXXVII Scheme 14 Step 1 [004121 To a solution of 1,3-dibromo-5-fluorobenzene (LXXIV) (4 g, 15.75 mmol) in toluene (50 mL) was added t BuOK (5.3 g, 47.25 mmol) and N ',NIN2 trimethylethane-1,2-diamine (2.778 mL, 31.5 mmol). The reaction was stirred at 110 0 C overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, 103 WO 2013/151708 PCT/US2013/031055 dried over MgSO 4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl 3 -+ 5:95 MeOH:CHCl 3 ) to produce N'-(3-bromo-5 fluorophenyl)-N 2
,N
2 -dimethylethane-1,2-diamine (LXXV) as a brown viscous oil (1.02 g, 3.91 mmol, 24.8% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.17 (s, 6H), 2.40 (t, J=3.5Hz, 2H), 3.01-3.09 (in, 2H), 6.10 (t, J=5Hz, 1H), 6.38 (dt, J=12Hz, J=2Hz, 1H), 6.51 (dt, J=8.5Hz, J=2Hz, 1H), 6.60 (s, 1H); ESIMS found C1 2 H1 6 BrFN 2 m/z 261 (M+H). Step 2-3 [004131 A solution of N'-(3-bromo-5-fluorophenyl)-N 2
,N
2 -dimethylethane-1,2 diamine (LXXV) (5 g, 19.15 mmol), bis(pinacolato)diboron (5.83 g, 22.98 mmol), KOAc (5.63 g, 57.45 mmol) and dry DMF (20 mL) was purged with argon. PdCl 2 (dppf) 2 (938 mg, 1.15 mmol) was added to the reaction and purged again with argon. The solution was heated at 95C for 2 h. Once TLC showed the disappearance of (LXXV), the solution was cooled to room temperature. To this solution was added K 3 P0 4 (6.09 g, 28.72 mmol), 3-bromo-5-nitropyridin-4-amine (LVIII) (4.17 g, 19.15 mmol), Pd(PPh 3
)
4 (663 mg, 0.57 mmol) and water (4 mL). The solution was purged with argon and heated at I 00 0 C for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between DCM and water. The aqueous phase was filtered through Celite* and concentrated under vacuum. The residue was purified on a silica gel column (100% CHCl 3 -- + 5:95 MeOH:CHCl 3 ) to give N'-(3-(4 amino-5-nitropyridin-3-yl)-5-fluorophenyl)-N 2
,N
2 -dimethylethane-1,2-diamine (LXXVII) as a yellow amorphous solid (3.30 g, 10.33 mmol, 54.0% yield for 2 steps). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.18 (s, 6H), 2.44 (t, J=6.5Hz, 2H), 3.12 (q, J=6Hz, 2H), 6.01 (t, J=5Hz, 1H), 6.35 (d, J=9Hz, 1H), 6.43 (s, 1H), 6.48 (dt, J=10Hz, J=2Hz, 1H), 7.32 (brs, 2H), 8.10 (s, IH), 9.01 (s, IH); ESIMS found for Ci 5 Hi 8
FN
5 0 2 m/z 320.3 (M+H). Step 4 [004141 To a solution of Nl-(3-(4-amino-5-nitropyridin-3-yl)-5-fluorophenyl) N2,N 2-dimethylethane-1,2-diamine (LXXVII) (2.1 g, 6.58 mmol) in MeOH (40 mL) was added 10% Pd/C (300 mg, 15% by w). The solution was purged with hydrogen and 104 WO 2013/151708 PCT/US2013/031055 stirred for 4 h at room temperature under hydrogen. The suspension was filtered through Celite* and concentrated under vacuum to produce 5-(3-(2-(dimethylamino)ethylamino) 5-fluorophenyl)pyridine-3,4-diamine (LXXVIII) as a brown solid (1.90 g, 6.57 mmol, 99.8% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.20 (s, 6H), 2.46 (t, J=7Hz, 2H), 3.12 (q, J=6Hz, 2H), 4.79 (s, 2H), 5.21 (s, 2H), 5.91 (t, J=5Hz, 1H), 6.28 (dd, J=9Hz, J=lHz, 1H), 6.36 (t, J=2Hz, 1H), 6.37-6.42 (m, 1H), 7.46 (s, 1H), 7.64 (s, 1H); ESIMS found C 15
H
2 0
FN
5 m/z 290.1 (M+H). 100415] Preparation of intermediate (LXXXIII) is depicted below in Scheme 15. 0 0 NH NH CHO
H
2
N-SO
2
CH
3 I0-I Br F NaBH(OAc),TEA Br F KOAc, PdC 2 (dppf) 2 B F DCE DMF, 90 0 C, 2 h LXXIX LXXX LXXXI
NH
2 0 2 N Br 0 0 LVHI g - N NH ONH K 3 P0 4 , Pd(PPh 3
)
4 H20, 90"C, 3 h N H 2
NH
2
H
2 N N F 10% Pd/C-H 2 0 2 N > F MeOHl N N LXXXIII LXXXII Scheme 15 Step 1 1004161 To a solution of 3-bromo-5-fluorobenzaldehyde (LXXIX) (2.03 g, 10.01 mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15.01 mmol) and TEA (2.79 mL, 20.02 mmol). NaBH(OAc) 3 (3.00 g, 14.13 mmol) was added and stirred at room temperature overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer sparated and washed with 105 WO 2013/151708 PCT/US2013/031055 water, brine, dried over MgSO 4 and evaporated under vacuum to produce N-(3-bromo-5 fluorobenzyl)methanesulfonamide (LXXX) as a colorless oil (2.653 g, 9.40 mmol, 93.9% yield). ESIMS found C 8
H
9 BrFNO 2 S m/z 282.0 (M+H). Step 2-4 [00417] Procedures can be found in Scheme 13, Steps 2-4. N-(3-(4,5 Diaminopyridin-3-yl)-5-fluorobenzyl)methanesulfonamide LXXXIII was isolated as a light tan solid (428.4 mg, 1.38 mmol, quantitative yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.92 (s, 3H), 4.24 (d, J=6.3Hz, 2H), 4.80 (s, 2H), 5.23 (s, 2H), 7.11-7.13 (m, 1H), 7.16-7.18 (m, 1H), 7.22 (s, IH), 7.47 (s, 1H), 7.64 (d, J=6.3Hz, 1H), 7.68 (s, 1H); ESIMS found C 13 Hi 5
FN
4 02S m/z 311 (M+H). Example 1. [004181 Preparation of compound (1) is depicted below in Scheme 16. 0 NH H Br N N 0- XXvlHI NBB N xii ' N KOAe, PdCI 2 (dppf) 2 b K2PO4 Pd(PPh)4 N DMF, 80 0 C, 2 h DMF, H20, 90 0 C, 3 h 0b 0 0b I LXXXIV NH, DN
H
2 N NH N N DMF, sulfur LX 140 0 C, ON N N O NH N O NHN N NH NH N Et 3 SiH, DCM N N TFA,r.t.,2h N H 1 0 cxxxvb Scheme 16 106 WO 2013/151708 PCT/US2013/031055 Step 1-2 [004191 A solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3 carbaldehyde (II) (498 mg, 1.4 mmol), bis(pinacolato)diboron (426 mg, 1.6 mmol), KOAc (412 mg, 4.2 mmol) and dry DMF (10 mL) was purged with nitrogen. Pd(dppf) 2 Cl 2 (68 mg, 0.08 mmol) was added to the reaction and purged again with nitrogen. The solution was heated at 90'C for 2 h. Once TLC showed the disappearance of (II), the solution was cooled to room temperature. To this solution was added K 3 P0 4 (446 mg, 2.1 mmol), N-(5-bromopyridin-3-yl)-3-methylbutanamide (XXVIII) (358 mg, 1.4 mmol), Pd(PPh 3
)
4 (48 mg, 0.042 mmol) and water (2 mL). The solution was purged with nitrogen and heated at 90 0 C for 4 h. The reaction was passed through a pad of Celite* and then concentrated under reduced pressure. The residue was suspended in water, sonicated, filtered and dried. The crude product was purified on a silica gel column (100% DCM -- 3:97 MeOH:DCM) to give N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2 yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide (LXXXIV) as an off white solid (239 mg, 0.59 mmol, 42% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.96 (d, 6H), 1.60-1.67 (in, 1H), 1.75-1.84 (in, 1H), 2.05-2.15 (in, 3H), 2.26 (d, 2H), 2.39-2.47 (in, IH), 3.80-3.86 (in, 1H), 3.89-3.93 (in, 1H), 6.13 (dd, 1H), 7.91 (dd, 1H), 8.06 (d, 1H), 8.36 (s, 1H), 8.39 (s, 1H), 8.63 (d, 1H), 8.81 (d, IH), 10.23 (s, 1H); ESIMS found
C
23
H
2 6
N
4 0 3 m/z 407.3 (M+H). Step 3-4 [00420] A solution of N-(5-(3-fornyl-1-(tetrahydro-2H-pyran-2-yl)-1H indazol-5-yl)pyridin-3-yl)-3-methylbutanamide (LXXXIV) (52 mg, 0.127 mmol), 5-(4 methylpiperazin-1-yl)pyridine-3,4-diamine (LVIII) (29 mg, 0.13 mmol) and sulfur (45 mg, 0.13 mmol) in dry DMF (10 mL) was heated at 140C overnight. The reaction was cooled and evaporated under vacuum. The viscous residue was dried overnight under vacuum. The solid was washed with cold water and dried under vacuum. The crude product (LXXXV) was dissolved in DCM (5 mL) followed by Et 3 SiH (48 tL, 0.30 mmol) and slowly addition of TFA (2.5 mL). The reaction was stirred until TLC (10% MeOH/DCM) showed the reaction was complete. The reaction was evaporated under vacuum and the residue was treated with water, sonicated and then basified with aq. 107 WO 2013/151708 PCT/US2013/031055 ammonia. The solids were filtered, washed with cold water and dried. The crude product was heated in EtOAc and filtered hot to remove impurities. The hot EtOAc solution was allowed to slowly cool to room temperature and filtered to give 3-methyl-N-(5-(3-(7-(4 methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3 yl)butanamide 1 as a pink solid (36 mg, 0.071 mmol, 59% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.97 (d, 6H), 2.13 (in, 1H), 2.27 (in, 4H), 3.45 (in, 4H), 6.70 (s, 1H), 7.79 (dd, 2H), 8.36 (s, 1H), 8.62 (s, 1H), 8.65 (s, 1H), 8.66 (s, IH), 8.84 (s, IH), 10.26 (s, 1H), 12.97 (s, 1H), 13.82 (s, 1H); ESIMS found for C 28
H
3 1
N
9 0 m/z 510.5 (M+H). [00421] The following compounds were prepared in accordance with the procedure described in the above Example 1. NN N/N 0 NHN NH N / N H 2 [00422] N-(5-(3 -(7-(4-methylpiperazin- 1 -yl)-3H-imidazo [4,5-c]pyridin-2-yl) 1H-indazol-5-yl)pyridin-3-yl)isobutyramide 2 [004231 Brick red solid (35% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.16 (d, 6H), 2.33 (brs, 3H), 2.58 (in, 4H), 2.64 (in, 1H), 3.49 (in, 4H), 6.71 (s, 1H), 7.79 (dd, 2H), 8.38 (s, 1H), 8.62 (s, 1H), 8.66 (s, 2H), 8.86 (dd, 1H), 10.23 (s, 1H), 12.99 (s, 1H), 13.83 (s, 1H); ESIMS found for C 27
H
2 9
N
9 0 m/z 496.4 (M+H).
-N/
N /N \NH N NN NN H 3 108 WO 2013/151708 PCT/US2013/031055 [00424] N,N-dimethyl-1-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5 c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine 3 [004251 Off white solid (63% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.22 (s, 6H), 2.24 (s, 3H), 2.46 (m, 4H), 3.45 (m, 4H), 3.55 (s, 2H), 6.69 (s, 1H), 7.81 (dd, 2H), 8.03 (s, 1H), 8.51 (d, 1H), 8.65 (s, 1H), 8.68 (s, 1H), 8.84 (d, 1H), 12.95 (brs, 1H), 13.81 (brs, 1H); ESIMS found for C 26
H
29
N
9 m/z 468.3(M+H). /N N N NH NCI\ ,N N N H 4 [00426] 7-(4-methylpiperazin-1-yl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H imidazo[4,5-c]pyridine 4 [00427] Light brown solid (51% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.24 (s, 3H), 2.56-2.67 (m, 4H), 3.43-3.54 (m, 4H), 6.72 (s, 1H), 7.55 (dd, 1H), 7.83 (dd, 2H), 8.16 (dd, 1H), 8.61 (dd, 1H), 8.66 (s, 1H), 8.70 (s, 1H), 8.96 (d, 1H), 13.00 (brs, 1H), 13.82 (s, 11); ESIMS found C 23
H
22
N
8 m/z 411.1 (M+H). CON N N NH IN -' N H 5 [00428] 4-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl) 1H-indazol-5-yl)pyridin-3-yl)morpholine 5 [004291 Off white solid (69% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.24 (s, 3H), 2.46 (m, 4H), 3.36 (m, 4H), 3.45 (m, 4H), 3.80 (t, 4H), 6.69 (s, 1H), 7.57 (s, 1H), 7.80 (dd, 2H), 8.35 (dd, 2H), 8.66 (d, 1H), 12.92 (brs, 1H), 13.76 (brs, 1H); ESIMS found C 27
H
29
N
9 O m/z 4.96.5 (M+H). 109 WO 2013/151708 PCT/US2013/031055 NN N N\ NH H 6 [00430] 4-(2-(5-(pyridin-3-yl)- 1 H-indazol-3-yl)-3H-imidazo[4,5-c]pyridin-7 yl)morpholine 6 [004311 Beige solid (65% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 3.41 (t, 4H), 3.76 (t, 4H), 6.75 (brs, 1H), 7.56 (dd, 1H), 7.83 (dd, 2H), 8.17 (dd, 1H), 8.62 (d, 1H), 8.66 (brs, 1H), 8.71 (s, 1H), 8.96 (s, 1H), 13.05 (brs, 1H), 13.84 (s, 1H); ESIMS found C 22 Hj 19
N
7 O m/z 398.0 (M+H). N N7 N NN H 7 [00432] 2-(5-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-lH-indazol-3-yl)-3H imidazo[4,5-c]pyridine 7 [004331 Off white solid (68% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.29 (s, 3H), 2.57 (m, 4H), 3.35 (m, 4H), 7.52 (brs, 1H), 7.57 (t, 1H), 7.81 (dd, 2H), 8.34 (m, 3H), 8.70 (s, 1H), 9.06 (brs, 1H), 13.45 (brs, 1H), 13.89 (brs, 1H); ESIMS found
C
23
H
22
N
8 m/z 410.9 (M+H). 0 NH O ~~ tNH NH NH N H 9 110 WO 2013/151708 PCT/US2013/031055 1004341 N-(5-(3-(3H-imidazo[4,5-c]pyridin-2-yl1)-H-indazol-5-yl)pyridin-3 yl)isobutyramide 9 [00435] Tan solid (63% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.16 (d, 6H), 2.67 (sep, 1H), 7.53 (d, 1H), 7.79 (dd, 2H), 8.34 (d, 1H), 8.40, (s, 1H), 8.63 (d, 1H), 8.70 (s, IH), 8.87 (s, 1H), 9.06 (s, IH), 10.27 (s, 1H), 13.49 (s, 11), 13.98 (s, 1H); ESIMS found C 22 H1 9
N
7 0 m/z 3.98.0 (M+H). F N NNH 6N NN H NN H 10 [004361 N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)-3-methylbutanamide 10 100437] White solid (98% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.98 (d, 6H), 2.13 (m, iH), 2.28 (d, 2H), 7.24 (t, IH), 7.60 (dd, IH), 7.84 (dd, 2H), 8.27 (d, 1H), 8.38 (d, 1H), 8.49 (s, 1H), 8.66 (s, 1H), 8.77 (s, 2H), 8.87 (d, 2H), 10.23 (s, IH), 13.81 (brs, 1H), 14.05 (s, 1H); ESIMS found C 2 9
H
24
FN
7 0 m/z 506.1(M+H). F NH 0N NH NN H NN N H 11 [00438] N-(5-(3-( 7
-(
2 -fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-y1)pyridin-3-yl)-3-methylbutanamide 11 [00439] White solid (37% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.98 (d, 6H), 2.13 (m, iH), 2.29 (d, 2H), 7.37-7.41 (m, 2H), 7.48-7.63 (m, 1H), 7.77-7.84 (m, 2H), 8.15 (m, 1H), 8.30-8.45 (m, 1H), 8.51-8.60 (dd, iH), 8.73 (dd, 1H), 8.85 (m, 2H), Il1 WO 2013/151708 PCT/US2013/031055 8.88 (s, 1H), 10.27 (m, 1H), 13.68 (brs, 1H), 14.93 (s, 1H); ESIMS found C 29
H
24
FN
7 0 m/z 506.3(M+H). N 0 NH N H NN N N H 12 [004401 N-(5-(3-(7-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)-3-methylbutanamide 12 [004411 White solid (50% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.98 (d, 6H), 2.17 (m, 1H), 2.32 (d, 2H), 7.40 (m, 2H), 7.84 (s, 2H), 8.45 (m, 2H), 8.58 (s, 1H), 8.67 (s, 2H), 8.72 (d, 1H), 8.83 (m, 2H), 10.30 (s, 1H), 13.71 (brs, 1H), 14.02 (s, 1H); ESIMS found C 29
H
24
FN
7 0 m/z 506.1(M+H). F N N H N /N SN' H 15 [004421 7-(3-fluorophenyl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H imidazo[4,5-c]pyridine 15 [004431 Brown solid (75% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 7.32 (td, 1H), 7.65 (m, 1H), 7.61 (dd, 1H), 7.85 d, 1H), 7.92 (d, 1H), 8.20 (d, 2H), 8.49 (d, 1H), 8.63 (dd, 1H), 8.78 (s, 1H), 8.88 (s, 1H), 8.94 (s, 1H), 9.03 (1H), 13.82 (brs, 1H), 14.02 (s, 1H); ESIMS found C 24 HisFN 6 m/z 407.3 (M+H). 112 WO 2013/151708 PCT/US2013/031055 F N N NN N\H NN H 16 [004441 1-(5-(3 -(7-(5-fluoropyridin-3 -yl)-3H-imidazo [4,5-c]pyridin-2-yl)- 1H indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 16 [004451 Off white solid (60% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.36 (brs, 6H), 3.69 (brs, 2H), 7.85 (d, 1H), 7.91 (d, IH), 8.07 (s, 1H), 8.56 (s, 1H), 8.67 (d, 1H), 8.83 (m, 3H), 8.92 (s, 2H), 9.49 (s, 1H), 13.86 (s, 1H), 14.06 (s, 1H); ESIMS found C 26
H
2 1
FN
8 m/z 465.0 (M+H). F N/ o N H N\ NH N /N ~ N/ H 20 [004461 N-(5-(3-(7-(5-fluoropyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)propionamide 20 [004471 Brown solid (63% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.13 (t, 3H), 2.41 (m, 2H), 7.81-7.87 (m, 2H), 8.45 (s, 1H), 8.65 (s, 2H), 8.78-8.93 (m, 4H), 9.40 (s, 1H), 10.20 (s, 1H), 13.91 (brs, 1H), 14.02 (s, 1H); ESIMS found C 26
H
1 9
FN
8 0 m/z 479.1 (M+H). 113 WO 2013/151708 PCT/US2013/031055 F NH NH N NNH N N H 24 [004481 N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-IH indazol-5-yl)pyridin-3-yl)propionamide 24 [00449] Tan solid (37.5 mg). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.14 (t, J=7.5Hz, 3H), 2.44 (q, J=7.5Hz, 2H), 7.28 (t, J=8Hz, 1H), 7.61 (q, J=8Hz, 1H), 7.84 (q, J=8.5Hz, 2H), 8.23 (brs, 1H), 8.35 (brs, 1H), 8.50 (s, 1H), 8.67 (s, 1H), 8.76 (s, 2H), 8.85 (s, 1H), 8.93 (brs, 1H), 10.24 (s, 1H), 14.07 (s, lH); ESIMS found C 27
H
2 0
FN
7 0 m/z 478.3 (M+H). F ,N o NH NH N H 31 [004501 N-(5-(3-(7-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)isobutyramide 31 [00451] Beige solid (27.5 mg, 20.3% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.17 (d, J=6.5Hz, 6H), 2.68 (sex, J=7Hz, 1H), 7.40-7.52 (m, 3H), 7.55-7.63 (m, 2H), 7.84 (dd, J=9Hz, J=1.5Hz, 1H), 7.90 (d, J=8.5Hz, 1H), 8.50 (brs, 1H), 8.62 (s, 1H1), 8.72 (s, 2H), 8.80 (brs, 1H), 10.27 (s, 1H), 13.09 (brs, 1H), 14.29 (brs, 1H); ESIMS found
C
28
H
22
FN
7 0 m/z 492.2 (M+H). 114 WO 2013/151708 PCT/US2013/031055 F NHN 0 NH N NH N ~ H 86 [004521 N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo [4,5-c]pyridin-2-yl)- 1 H indazol-5-yl)pyridin-3-yl)-2-phenylacetamide 86 [004531 Beige solid (14.1 mg, 16.1% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 3.76 (s, 2H), 7.18 (t, J=6.5Hz, 1H), 7.27 (t, J=7.5Hz, 1H), 7.29-7.42 (m, 4H), 7.81 (d, J=7.5Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 8.25 (d, J=7.5Hz, 1H), 8.36 (d, J=11Hz, 1H), 8.50 (s, 1H), 8.66 (s, 1H), 8.76 (s, 1H), 8.77 (s, 1H), 8.86 (d, J=3Hz, 1H), 10.56 (s, 1H), 13.77 (s, 1H), 14.04 (s, IH); ESIMS found C 32
H
22
FN
7 0 m/z 540.5 (M+H). F N N\ NH NN N H 89 [004541 1-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 89 [00455] Light brown solid (16.1 mg, 19.0% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.30 (brs, 9H), 3.69 (brs, 2H), 7.31 (dt, J=2.5Hz, J=8.5Hz, 1H), 7.61 (q, J=7.5Hz, 1H), 7.85 (d, J=9Hz, 1H), 7.91 (d, J=9Hz, 1H), 8.08 (brs, 1H), 8.23 (d, J=7.5Hz, 1H), 8.32 (d, J=7Hz, 1H), 8.40 (s, 1H), 8.76 (s, 1H), 8.88 (d, J=7.5Hz, 2H), 8.99 (s, 1H), 13.78 (brs, 1H), 14.04 (brs, 1H); ESIMS found C 2 7
H
22
FN
7 m/z 463.9 (M+H). 115 WO 2013/151708 PCT/US2013/031055 F NN N\NH N H 90 [004561 N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide 90 [00457] Light brown solid (10.5 mg, 5.9% yield). 'H NMR (DMSO-d 6 , 500 MHz,) 6 ppm 1.06 (s, 9H), 2.28 (s, 2H), 7.24 (dt, J=8.5Hz, J=2Hz, 1H), 7.59 (q, J=8Hz, 1H), 7.81 (d, J=8.5Hz, 1H), 7.86 (d, J=8,5Hz, 1H), 8.26 (d, J=8Hz, 1H), 8.38 (d, J=1lHz, 1H), 8.49 (s, 1H), 8.66 (d, J=1.5Hz, 1H), 8.77 (dd, J=5.5Hz, J=2Hz, 2H), 8.87 (d, J=8Hz, 2H), 10.17 (s, 1H), 13.78 (s, 1H), 14.04 (s, 1H); ESIMS found C 30
H
26
FN
7 0 m/z 520.3 (M+H). F O NH N \ NH N \N H 91 100458] N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide 91 [00459] Yellow white solid (3.7 mg, 1.5% yield). IH NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.92-0.97 (m, 2H), 1.01-1.06 (m, 2H), 1.86 (quin, J=4.5Hz, 1H), 7.18 (dt, J=8Hz, J=2Hz, IH), 7.56 (q, J=8Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 7.76 (dd, J=8.5Hz, J=1.5Hz, 1H), 7.86-8.10 (m, 2H), 8.47 (t, J=2.5Hz, 1H), 8.50 (brs, 1H), 8.62 (d, J=2Hz, 1H), 8.74 (d, J=2.5Hz, 1H), 8.82 (s, 2H); ESIMS found C 2 8
H
2 0
FN
7 0 m/z 489.8 (M+H). 116 WO 2013/151708 PCT/US2013/031055 F /N 0 NH N \NH H 94 [004601 N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide 94 [004611 Light brown solid (27.6 mg, 29.0% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.16-1.25 (m, 1H), 1.31 (q, J=12.5Hz, 2H), 1.45 (q, J=12Hz, 2H), 1.67 (d, J=11.5Hz, 1H), 1.79 (d, J=12.5Hz, 2H), 1.88 (d, J=12Hz, 2H), 2.41 (dq, J=8Hz, J=3Hz, 1H), 7.22 (dt, J=8Hz, J=2Hz, 1H), 7.60 (q, J=7.5Hz, 1H), 7.84 (q, J=9Hz, 2H), 8.28 (d, 8Hz, 1H), 8.39 (t, J=11Hz, 1H), 8.51 (s, 1H), 8.66 (d, J=1.5Hz, 1H), 8.77 (s, 2H), 8.86 (d, J=6Hz, 2H), 10.17 (s, 1H), 13.77 (s, 1H), 14.04 (s, 1H); ESIMS found C 3 nH 2 6
FN
7 0 m/z 532.2 (M+H). F/\ / NH, N I\ NH N N SN' H 97 [00462] 5-(3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-IH-indazol 5-yl)pyridin-3-amine 97 [004631 Tan solid (51.0 mg). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 5.53 (brs, 2H), 7.31-7.42 (m, 3H), 7.78 (q, J=8Hz, 1H), 7.99 (d, J=2Hz, 1H), 8.16 (s, 1H), 8.23 (brs, 1H), 8.46 (brs, 2H), 8.67 (s, 1H), 8.84 (s, 2H), 13.72 (brs, 1H), 14.02 (brs, 1H); ESIMS found C 24
H
16
FN
7 m/z 422.0 (M+H). 117 WO 2013/151708 PCT/US2013/031055 F N \NH N ~ N SN H 99 [004641 7
-(
4 -Fluorophenyl)-2-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-3H imidazo[4,5-c]pyridine 99 [00465] Light brown solid (18.2 mg, 14.2% yield). 'H NMR (DMSO-do, 500 MHz) 6 ppm 2.39 (s, 3H), 7.36 (t, J=8.5Hz, 2H), 7.50 (d, J=5Hz, 1H), 7.62 (dd, J=8.5Hz, J=1.5Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 8.28 (brs, 2H), 8.54 (d, J=3.5Hz, 2H), 8.58 (s, 1H), 8.71 (s, 1H), 9.06 (brs, 1H), 14.21 (s, 1H); ESIMS found C 25
H
17
FN
6 m/z 421.0 (M+H). F o NHF NN H N N N N H 102 [004661 N-(5-(3-( 7 -(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)pivalamide 102 [00467] Tan solid (66.3 mg). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.30 (s, 9H), 7.38 (t, J=8.5Hz, 2H), 7.85 (s, 2H), 8.48 (brs, 2H), 8.62 (brs, 1H), 8.67 (s, 2H), 8.83 (s, IH), 8.85 (brs, 1H), 8.90 (s, 1H), 9.62 (s, 1H), 13.76 (brs, 1H), 14.03 (s, 1H); ESIMS found C 29
H
24
FN
7 0 m/z 506.1 (M+H). NN o NH NN N \NH N H 104 118 WO 2013/151708 PCT/US2013/031055 [00468] N-(5-(3-(7-(4-Fluorophenyl)-3H-imidazo[ 4 ,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)benzamide 104 1004691 Light brown solid (1.1 mg, 0.002 mmol, 2.4% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 7.39 (t, J=9Hz, 2H), 7.59 (t, J=7.5Hz, 2H), 7.65 (d, J=7Hz, 1H), 7.89 (s, 2H), 8.06 (dd, J=lHz, J=8.5Hz, 2H), 8.47 (brs, 2H), 8.70 (brs, 1H), 8.75 (s, 1H), 8.88 (s, 1H), 8.91 (brs, 1H), 8.99 (s, 1H), 10.69 (s, 1H), 14.12 (s, 1H); ESIMS found
C
3 1
H
2 0
FN
7 0 m/z 526.3 (M+H). F N N\ H N N 107 [004701 7-(4-Fluorophenyl)-2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H indazol-3-yl)-3H-imidazo[4,5-c]pyridine 107 [00471] Brown solid (12.7 mg, 57% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.71 (brs, 4H), 2.47-2.56 (m, 4H), 3.76 (s, 2H), 7.41 (t, J=9Hz, 2H), 7.83 (d, J=8.5Hz, 1H), 7.93 (d, J=9Hz, 1H), 8.07 (s, 1H), 8.45 (t, J=6Hz, 2H), 8.56 (s, 1H), 8.66 (s, 1H), 8.84 (s, 1H), 8.90 (s, 1H), 8.92 (s, 1H), 13.72 (brs, 1H), 14.00 (brs, 1H); ESIMS found C 2 9
H
24
FN
7 m/z 490.2 (M+H). F 7N o NH N NN N H 111 [004721 N-(5-(3-( 7 -(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide 111 [00473] Brown solid (4.1 mg, 0.008 mmol, 22.0% yield). ' H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.25-1.36 (m, 1H), 1.43-1.53 (m, 1H), 1.77-1.88 (m, 1H), 1.93-2.02 (m, 1H), 2.13-2.22 (m, 1H), 2.25-2.34 (m, 1H), 2.84-2.95 (m, 1H), 7.35 (brs, 2H), 7.40 (t, 119 WO 2013/151708 PCT/US2013/031055 J=9Hz, 2H), 7.84 (s, 2H), 8.19 (brs, 1H), 8.47 (brs, 1H), 8.63 (brs, 1H), 8.66 (d, J=1.5Hz, 1H), 8.73 (brs, 1H), 8.84 (brs, 1H), 10.17 (s, 1H), 13.74 (brs, 1H); ESIMS found
C
29
H
22 FN70 m/z 504.1 (M+H). F NH NNH /N -~N H 124 [004741 5-(3-(7-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol 5-yl)-N-isopropylpyridin-3-amine 124 [00475] Tan solid (11.1 mg, 0.024 mmol). H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.14-1.26 (m, 6H), 3.59-3.77 (m, 1H), 5.80-5.90 (m, 1H), 7.10, 7.20 (2 rotamers, iH), 7.32-7.43 (m, 2H), 7.48-7.59 (m, 1H), 7.77 (s, 2H), 8.03-8.13 (m, 1H), 8.30, 8.49 (2 rotamers, 1H), 8.68, 8.69 (2 rotamers, 1H), 8.88, 9.10 (2 rotamers, 1H), 13.66, 13.68 (2 rotamers, 1H), 13.87, 13.94 (2 rotamers, 1H); ESIMS found C 27
H
22
FN
7 m/z 463.9 (M+H). F N N N NH ""N SN/ H 127 100476] 7-(2-Fluorophenyl)-2-(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H indazol-3-yl)-3H-imidazo[4,5-clpyridine 127 [004771 Brown solid (53.7 mg, 39% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.36-1.57 (m, 6H), 2.42 (m, 4H), 3.61 (s, 2H), 7.35-7.46 (m, 2H), 7.50-7.58 (m, 1H), 7.82 (d, J=9Hz, 1H), 7.88 (d, J=7.5Hz, 1H), 7.97 (s, 1H), 8.16 (t, J=8Hz, 1H), 8.52 (d, J=7.5Hz, 2H), 8.79 (s, IH), 8.86 (s, 1H), 13.71 (s, 1H), 13.99 (s, 1H); ESIMS found
C
30
H
26
FN
7 m/z 504.3 (M+H). 120 WO 2013/151708 PCT/US2013/031055 N N N NH N N~ N H 136 [00478] 7-(Pyridin-3-yl)- 2 -(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5 c]pyridine 136 [004791 Light brown solid (35.1 mg, 51.5% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 7.56-7.64 (m, 2H), 7.85 (d, J=8.5Hz, 1H), 7.90 (d, J=10Hz, 1H), 8.19 (td, J=1.5Hz, J=8Hz, 1H), 8.64 (dd, J=4.5Hz, J=1.5Hz, 1H), 8.69 (dd, J=5Hz, J=1.5Hz, 1H), 8.77 (brs, 2H), 8.86 (s, 1H), 8.95 (brs, 1H), 9.01 (d, J=1.5Hz, 1H), 9.52 (brs, 1H), 14.06 (s, 1H); ESIMS found C 23
H
15
N
7 m/z 389.8 (M+H). N N N\ NH N .- N N H 154 [00480] 2-(5-(4-Methylpyridin-3-yl)-l1H-indazol-3-yl)-7-(pyridin-4-yl)-3H imidazo[4,5-c]pyridine 154 [004811 Light yellow solid (2.7 mg, 3.0% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.42 (s, 3H), 7.45 (d, J=5Hz, 1H), 7.61 (d, J=9Hz, 1H), 7.83 (d, J=8.5Hz, 1H), 8.36 (d, J=5.5Hz, 2H), 8.50 (d, J=5.5Hz, 1H), 8.56 (s, 1H), 8.61 (s, 1H), 8.65 (d, J=5Hz, 1H), 8.81 (s, 1H), 8.92 (s, 1H), 13.85 (s, 1H), 14.05 (s, 1H); ESIMS found
C
24 H1 7
N
7 n/z 404.1 (M+H). N N NNH N -~N H 163 121 WO 2013/151708 PCT/US2013/031055 100482] 7-(Pyridin-4-yl)-2-(5-(5-(pyrrolidin- 1 -ylmethyl)pyridin-3-yl)-1H indazol-3-yl)-3H-imidazo[4,5-clpyridine 163 [004831 Brown solid (9.7 mg, 70% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.73 (brs, 4H), 2.51-2.62 (m, 4H), 3.76 (s, 2H), 7.85 (d, J=8.5Hz, 1H), 7.94 (d, J=9Hz, 1H), 8.11 (s, 1H), 8.47 (d, J=4Hz, 2H), 8.56 (s, IH), 8.77 (d, J=4Hz, 2H), 8.85 (s, 1H), 8.93 (brs, 3H), 13.85 (brs, 1H), 14.04 (brs, 1H); ESIMS found C 28
H
24
N
8 m/z 473.3 (M+H). N N \ NH N /N _~N H 164 [004841 2-(5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-7 (pyridin-4-yl)-3H-imidazo[4,5-c]pyridine 164 [00485] Brown solid (70 mg, 73% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.40 (brs, 2H), 1.51 (brs, 4H), 2.43 (brs, 4H), 3.63 (brs, 2H), 7.85 (d, J=8.5Hz, 1H), 7.92 (d, J=8.5Hz, 1H), 8.08 (s, 1H), 8.46 (d, J=5.5Hz, 2H), 8.54 (s, 1H), 8.76 (d, J=5.5Hz, 2H), 8.84 (s, 1H), 8.90-8.97 (m, 3H), 13.85 (brs, IH), 14.04 (brs, IH); ESIMS found C 29
H
2 6
N
8 m/z 487.1 (M+H). O NH N N' H 170 [00486] N-(5-(3-(7-(Pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol 5-yl)pyridin-3-yl)cyclopentanecarboxamide 170 1004871 Tan solid (30.2 mg, 0.06 mmol). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.54-1.65 (m, 2H), 1.65-1.76 (m, 2H), 1.76-1.87 (m, 2H), 1.88-1.98 (m, 2H), 2.88 (quin, J=8Hz, 1H), 7.86 (s, 2H), 8.46 (d, J=4.5Hz, 2H), 8.66 (s, 1H), 8.68 (s, lH), 8.70 122 WO 2013/151708 PCT/US2013/031055 8.77 (m, 3H), 8.86 (s, 1H), 8.88 (s, 1H), 8.93 (s, 1H), 10.30 (s, 1H), 13.86 (brs, 1H), 14.06 (s, 1H); ESIMS found C 29
H
24
N
8 0 m/z 501.2 (M+H). N N HN NP \-NH N -~NN H 173 [00488 1 -Cyclopentyl-N-((5-(3-(7-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-2 yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine 173 100489] Brown solid (1.7 mg, 0.003 mmol, 2.5% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.41-1.63 (m, 8H), 1.79 (brs, 1H), 3.01 (brs, 2H), 4.34 (brs, 2H), 7.84 7.89 (m, 1H), 7.92 (d, J=5.5Hz, 1H), 8.41 (s, 1H), 8.47 (d, J=6Hz, 2H), 8.75 (s, 1H), 8.76 (d, J=6Hz, 2H), 8.86 (s, 1H), 8.94 (s, 1H), 8.98 (s, 1H), 9.11 (s, 1H), 13.81 (brs, 1H), 14.11 (s, IH); ESIMS found C 3 0
H
28
N
8 m/z 501.3 (M+H). /N 0 NH N\ NH 'N /N /' N H 174 [004901 N-(5-(3-(7-(Pyridin-2-yl)-3H-imidazo[4,5-clpyridin-2-yl)-1H-indazol 5-yl)pyridin-3-yl)propionamide 174 [004911 Tan solid (40.1 mg). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.15 (t, J=7.5Hz, 3H), 2.44 (q, J=7Hz, 2H), 7.47 (brs, 1H), 7.89 (s, 2H), 8.03 (t, J=7.5Hz, 1H), 8.59 (brs, 1H), 8.69 (s, 1H), 8.75(brs, 1H), 8.83 (brs, 1H), 9.03 (brs, 1H), 9.21 (brs, 2H), 10.30 (s, 1H), 14.10 (s, 1H); ESIMS found C 26
H
2 0
N
8 0 m/z 461.1 (M+H). /N /N N H H 123 WO 2013/151708 PCT/US2013/031055 177 [004921 7-(Pyridin-2-yl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5 c]pyridine 177 100493] White solid (32.4 mg, 41.6% yield). 'H NMR (DMSO-d 6 , 500 MHz) 8 ppm 7.51 (dd, J=7Hz, J=5Hz, 1H), 7.61 (dd, J=7.5Hz, J=5Hz, 1H), 7.87 (d, J=8.5Hz, 1H), 7.92 (d, J=9Hz, 1H), 8.02 (t, J=7.5Hz, 1H), 8.23 (d, J=8Hz, 1H), 8.65 (d, J=4Hz, 1H), 8.84 (brs, 1H), 8.90 (brs, 1H), 9.05 (brs, 2H), 9.20 (brs, 2H), 14.09 (s, 1H); ESIMS found C 23
H
15
N
7 m/z 390.2 (M+H). NH NN N N ~ N H 186 [004941 NN-Dimethyl-I -(5-(3-(7-(pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-2 yl)-lH-indazol-5-yl)pyridin-3-yl)methanamine 186 [004951 Light brown solid (18.4 mg, 25.8% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.84 (s, 6H), 4.47 (s, 2H), 7.52 (dd, J=6.5Hz, J=4.5Hz, 1H), 7.92 (s, 2H), 8.02 (t, J=7Hz, 1H), 8.38 (s, 1H), 8.73 (s, 1H), 8.80-9.26 (m, 6H), 14.17 (brs, 1H); ESIMS found C 26
H
22
N
8 m/z 447.0 (M+H). H N /N NH NP \NH H 199 [00496] 3-Methyl-N-(5-(3-(7-(piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl) 1H-indazol-5-yl)pyridin-3-yl)butanamide 199 [004971 Brown solid (22.7 mg, 22.2% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.98 (d, J=6.5Hz, 6H), 1.52-1.64 (m, 6H), 2.13 (sep, J=7Hz, 1H), 2.28 (d, J=7.5Hz, 2H), 3.38-3.52 (m, 4H), 6.67 (s, 1H), 7.79 (s, 2H), 8.36 (d, J=2.5Hz, 1H), 8.63 124 WO 2013/151708 PCT/US2013/031055 (dd, J=5Hz, J=2Hz, 2H), 8.66 (s, 1H), 8.85 (d, J=2Hz, 1H), 10.26 (s, 1H), 12.88 (s, 1H), 13.80 (s, 1H); ESIMS found C 2 8
H
30
N
8 0 m/z 495.4 (M+H). N N NP N( NH N N H 202 1004981 2-(5-(4-Methylpyridin-3-yl)-1H-indazol-3-yl)-7-(piperidin-1-yl)-3H imidazo[4,5-c]pyridine 202 [004991 White solid (1.5 mg, 1.1% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.65 (brs, 6H), 2.38 (s, 3H), 3.51 (brs, 4H), 7.02 (brs, 1H), 7.59 (dd, J=9Hz, J=1.5Hz, IH), 7.65 (d, J=5Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 8.43 (s, 1H), 8.64 (brs, 2H), 8.71 (brs, 1H), 13.76 (brs, 1H), 14.21 (s, 1H); ESIMS found C 24
H
23
N
7 m/z 410.1 (M+H). CN/N 0 NH N H N N N N' H 205 [005001 N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)pivalamide 205 [005011 Tan solid (66.5 mg). 'H NMR (DMSO-d 6 , 500 MHz) S ppm 1.29 (s, 9H), 1.60 (brs, 6H), 3.48 (brs, 4H), 6.67 (s, 1H), 7.80 (s, 2H), 8.41 (t, J=2Hz, 1H), 8.63 (d, J=1.5Hz, 1H), 8.64 (s, 1H), 8.67 (s, IH), 8.97 (d, J=2Hz, 1H), 9.59 (s, 1H), 12.89 (s, 1H), 13.81 (s, 1H); ESIMS found C 2 8
H
30
N
8 0 m/z 495.5 (M+H). N N N N N H 211 125 WO 2013/151708 PCT/US2013/031055 [005021 7-(Piperidin-1 -yl)-2-(5-(5-(pyrrolidin- 1 -ylmethyl)pyridin-3 -yl)-1 H indazol-3-yl)-3H-imidazo[4,5-c]pyridine 211 [00503] Brown solid (17.1 mg, 53% yield). 'H NMR (DMSO-d,, 500 MHz) 6 ppm 1.61 (brs, 6H), 1.74 (brs, 4H), 2.48-2.56 (m, 4H), 3.48 (brs, 4H), 3.75 (s, 2H), 6.67 (s, IH), 7.81 (q, J=9.5Hz, 2H), 8.04 (s, 1H), 8.53 (s, 1H), 8.63 (s, IH), 8.68 (s, 1H), 8.84 (s, 1H), 12.88 (brs, 1H), 13.79 (brs, 1H); ESIMS found C 28
H
30
N
8 m/z 479.3 (M+H). O NH N N NH N N H 214 [005041 N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)butyramide 214 [00505] Brown solid (33.2 mg, 0.069 mmol). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.96 (t, J=7.5Hz, 3H), 1.61 (brs, 6H), 1.66 (sex, J=7.5Hz, 2H), 2.38 (t, J=7.5Hz, 2H), 3.48 (brs, 4H), 6.67 (s, 1H), 7.79 (s, 2H), 8.36 (s, 1H), 8.62 (s, 1H), 8.63 (s, 1H), 8.66 (s, 1H), 8.85 (d, J=1.5Hz, 1H), 10.27 (s, 1H), 12.88 (s, 1H), 13.80 (s, 1H); ESIMS found C 2 7
H
28 NSO m/z 481.0 (M+H). N N/N NH N N H 217 [005061 N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide 217 [00507] Beige solid (12 mg, 0.024 mmol, 46.9% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.61 (brs, 6H), 1.80-1.88 (m, 1H), 1.93-2.04 (m, 1H), 2.11-2.21 (m, 2H), 2.22-2.33 (m, 2H), 3.26-3.32 (m, 1H), 3.48 (brs, 4H), 6.67 (s, 1H), 7.79 (s, 2H), 8.37 126 WO 2013/151708 PCT/US2013/031055 (d, J=2Hz, 1H), 8.62 (d, J=2Hz, 1H), 8.64 (s, 1H), 8.66 (s, 1H), 8.87 (d, J=2Hz, 1H), 10.12 (s, 1H), 12.88 (s, 1H), 13.80 (s, 1H); ESIMS found C 28
H
28
N
8 0 m/z 493.2 (M+H). NN N/N
NH
2 NN N NH -~N H 247 [005081 5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H indazol-5-yl)pyridin-3-amine 247 100509] Tan solid (9.6 mg). 'H NMR (DMSO-d 6 , 500 MHz) a ppm 2.36 (s, 3H), 2.44-2.56 (m, 4H), 3.46 (brs, 4H), 5.50 (s, 2H), 6.70 (s, 1H), 7.26 (t, J=2Hz, 1H), 7.65-7.76 (m, 2H), 7.96 (d, J=2Hz, 1H), 8.09 (d, J=1.5Hz, 1H), 8.62 (s, 1H), 8.65 (s, 1H), 12.95 (s, 1H), 13.76 (s, 1H); ESIMS found C 2 3
H
23
N
9 m/z 426.4 (M+H). N O NH N NH N w N H 252 [005101 N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl) 1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide 252 [00511] Beige solid (7.0 mg, 4.5% yield). 'H NMR (DMSO-d 6 , 500 MHz) a ppm 2.24 (s, 3H), 2.46 (brs, 5H), 3.45 (brs, 3H), 3.74 (s, 2H), 6.69 (s, 1H), 7.27 (t, J=5.5Hz, 1H), 7.32-7.41 (m, 4H), 7.79 (s, 2H), 8.36 (s, 1H), 8.64 (s, 2H), 8.66 (s, 1H), 8.86 (d, J=2.5Hz, 1H), 10.58 (s, 1H), 12.96 (s, 1H), 13.82 (s, 1H); ESIMS found
C
3 1
H
29
N
9 0 m/z 544.2 (M+H). 127 WO 2013/151708 PCT/US2013/031055 NN N/N 0 NH N N\ H N N H 257 [005121 3,3 -Dimethyl-N-(5 -(3 -(7-(4-methylpiperazin- 1 -yl)-3H-imidazo[4,5 c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 257 [005131 White solid (65.7 mg, 23.0% yield). 'H NMR (DMSO-d 6 , 500 MHz) 5 ppm 1.06 (s, 9H), 2.24 (s, 4H), 2.28 (s, 2H), 2.46 (brs, 4H), 3.45 (brs, 3H), 6.69 (s, 1H), 7.79 (ABq, J=10.5Hz, 2H), 8.37 (t, J=2Hz, 1H), 8.65 (dt, J=9.5Hz, J=2Hz, 3H), 8.85 (d, J=2Hz, IH), 10.2 (s, 1H), 12.97 (s, 1H), 13.82 (s, 1H); ESIMS found C 2 9
H
33
N
9 0 m/z 524.3 (M+H). NN N /N OXNH NH NN N H 260 [005141 N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl) 1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide 260 [00515] Brown solid (30.0 mg, 15.1% yield). 'H NMR (DMSO-d 6 , 500 MHz) S ppm 0.83-0.91 (m, 4H), 1.80-1.87 (m, 1H), 2.24 (s, 3H), 2.47 (brs, 5H), 3.45 (brs, 3H), 6.69 (s, 1H), 7.78 (ABq, J=9Hz, 2H), 8.36 (d, J=2Hz, 1H), 8.62 (d, J=2Hz, 1H), 8.66 (d, J=2Hz, 2H), 8.84 (d, J=2Hz, 1H), 10.60 (s, 1H), 12.96 (s, 1H), 13.82 (s, 1H); ESIMS found C 2 7
H
27
N
9 0 m/z 494.4 (M+H). NN o NH HN N NH NN N H 128 WO 2013/151708 PCT/US2013/031055 263 [005161 N-(5-(3 -(7-(4-Methylpiperazin- 1 -yl)-3H-imidazo[4,5-c]pyridin-2-yl) 1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide 263 [00517] Brown solid (1.7 mg, 2.2% yield). 'H NMR (DMSO-d 6 , 500 MHz) S ppm 1.16-1.26 (m, 5H), 1.31 (q, J=12.5Hz, 2H), 1.45 (q, J=9.5Hz, 3H), 1.67 (d, J=12Hz, 1H), 1.78 (d, J=18Hz, 2H), 1.87 (d, J=12Hz, 2H), 2.23-2.51 (m, 6H), 3.44 (brs, 3H), 6.70 (1H), 7.79 (ABq, J=13.5Hz, 2H), 8.38 (s, 1H), 8.60 (d, J=2Hz, 1H), 8.64 (d, J=4Hz, 2H), 8.84 (d, J=2Hz, 1H), 10.20 (s, 1H), 12.99 (brs, 1H), 13.82 (s, 1H); ESIMS found
C
30
H
33
N
9 0 m/z 536.3 (M+H). /N
NH
2 NP N N H N 'N N N' H 268 [005181 5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3 amine 268 [005191 Tan solid (81.6 mg). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 7.54 (brs, 1H), 7.81 (dd, J=8.5Hz, J=1.5Hz, 1H), 7.89 (d, J=9Hz, 1H), 8.02 (d, J=2.5Hz, 2H), 8.24 (s, 1H), 8.56 (d, J=6Hz, 1H), 8.68 (s, 1H), 14.31 (s, 1H); ESIMS found C 18
H
13
N
7 m/z 328.1 (M+H). N O NH NN SNH H 274 [00520] N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3 yl)-2-phenylacetamide 274 [005211 Beige solid (19.0 mg, 10.3% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 3.74 (s, 2H), 7.27 (t, J=7Hz, 1H), 7.32-7.40 (m, 4H), 7.52 (d, J=5.5Hz, 1H), 7.81 (ABq, J=11.5Hz, 2H), 8.34 (d, J=5.5Hz, 1H), 8.38 (t, J=2Hz, 1H), 8.65 (d, J=2Hz, 1H), 129 WO 2013/151708 PCT/US2013/031055 8.86 (d, J=1.5Hz, 1H), 9.05 (s, 1H), 10.58 (s, 1H), 13.48 (brs, 1H), 13.95 (brs, 1H); ESIMS found C 26
H
19
N
7 0 m/z 446.3 (M+H). 0 NH N /N N H 275 [00522] N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-IH-indazol-5-yl)pyridin-3 yl)benzamide 275 [00523] Light brown solid (2.1 mg, 0.005 mmol, 3.1% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 7.57 (dt, J=2Hz, J=7.5Hz, 2H), 7.64 (dd, J=2.5Hz, J=7.5Hz, 2H), 7.86 (s, 2H), 8.05 (dd, J=1.5Hz, J=8.5Hz, 2H), 8.35 (d, J=5.5Hz, 1H), 8.57 (dt, J=2Hz, J=4Hz, 1H), 8.72 (d, J=2Hz, 1H), 8.76 (s, 1H), 9.04 (d, J=2Hz, 1H), 9.09 (d, J=2Hz, 1H), 10.64 (s, 1H), 14.02 (s, 1H); ESIMS found C 25
H
17
N
7 0 m/z 432.3 (M+H). N \NH NN N H NN ~ N' H 280 [00524] N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3 yl)-3,3-dimethylbutanamide 280 1005251 Light brown solid (12.2 mg, 10.9% yield). 1 H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.07 (s, 9H), 2.29 (s, 2H), 7.85 (dd, J=9Hz, J=1.5Hz, 1H), 7.92 (d, J=8.5Hz, 1H), 8.06 (brs, 1H), 8.49 (s, 1H), 8.62 (d, J=6.5Hz, 1H), 8.67 (dd, J=7Hz, J=1.5Hz, 2H), 8.82 (d, J=1.5Hz, 1H), 9.58 (brs, 1H), 10.28 (s, IH), 14.35 (s, 1H), 14.78 (brs, 1H); ESIMS found C 24
H
2 3 N70 m/z 426.1 (M+H). 130 WO 2013/151708 PCT/US2013/031055 OJ NH N NH N 'N H 283 [005261 N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)- 1 H-indazol-5-yl)pyridin-3 yl)cyclopropanecarboxamide 283 [005271 Yellow white solid (5.7 mg, 2.3% yield). 1H NMR (CD 3 0D, 500 MHz) 6 ppm 0.91-0.96 (m, 2H), 1.02-1.07 (m, 2H), 1.86 (quin, J=3.5Hz, 1H), 7.21 (sd, J=1.5Hz, 1H), 7.69 (t, J=1.5Hz, 1H), 7.73 (d, J=8.5Hz, 1H), 7.78 (dd, J=7.5Hz, J=1.5Hz, 1H), 8.50 (s, 1H), 8.59 (t, J=2Hz, 1H), 8.65 (d, J=2Hz, 2H), 8.71 (d, J=2Hz, 2H), 8.84 (s, 1H); ESIMS found C 22 H1 7
N
7 0 m/z 396.3 (M+H). 0 NHN NN NN H 286 [00528] N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-IH-indazol-5-yl)pyridin-3 yl)cyclohexanecarboxamide 286 [005291 Light brown solid (31.2 mg, 13.3% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.16-1.34 (m, 3H), 1.45 (dq, J=12.5Hz, J=3Hz, 2H), 1.67 (d, J=17Hz, IH), 1.79 (d, J=13Hz, 2H), 1.87 (d, J=12.5Hz, 2H), 2.41 (t of quin, J=11.5Hz, J=3.5Hz, 1H), 7.53 (brs, 1H), 7.82 (dq, J=9Hz, J=1.5Hz, 2H), 8.34 (d, 5Hz, 1H), 8.40 (t, J=2Hz, 1H), 8.62 (d, J=2Hz, 1H), 8.70 (s, 1H), 8.85 (d, J=2Hz, 1H), 9.07 (brs, 1H), 10.21 (s, 1H), 13.51 (brs, 1H), 13.99 (s, 1H); ESIMS found C 2 5
H
23
N
7 0 m/z 438.0 (M+H). 131 WO 2013/151708 PCT/US2013/031055 S N/N 0 NH N \NN N>\N ~ N/ H 289 [00530] N-(5-(3-(7-(Thiophen-3 -yl)-3H-imidazo[4,5-c]pyridin-2-yl)- 1IH indazol-5-yl)pyridin-3-yl)propionamide 289 [005311 Tan solid (24.9 mg). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.16 (t, J=7.5Hz, 3H), 2.46 (q, J=7.5Hz, 2H), 7.76 (dd, J=4.5Hz, J=3Hz, 1H), 7.88 (s, 2H), 8.15 (brs, 1H), 8.65 (brs, 1H), 8.69 (s, 1H), 8.71 (s, 1H), 8.78 (brs, 1H), 8.82-8.93 (m, 3H), 10.30 (s, 1H), 14.13 (s, 1H); ESIMS found C 2 5
H
19
N
7 0S m/z 466.2 (M+H). NH N
NH
2 N NH N N H 291 [00532] 5-(3-(7-(Thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol 5-yl)pyridin-3-amine 291 [005331 Tan (11.9 mg). ' H NMR (DMSO-d 6 , 500 MHz) 6 ppm 5.49 (s, 2H), 7.31 (s, 1H), 7.70-7.83 (m, 3H), 7.99 (s, 1H), 8.17 (s, 1H), 8.22 (d, J=4.5Hz, 1H), 8.74 (s, 1H), 8.78 (s, 1H), 8.82 (s, 1H), 8.83 (s, IH), 13.67 (s, 1H), 13.97 (s, 1H); ESIMS found
C
22 Hi 5
N
7 S m/z 410.1 (M+H). S N N, \ NH N 1 3 N SN' H 293 [005341 2-(5-(4-Methylpyridin-3-yl)-1H-indazol-3-yl)-7-(thiophen-3-yl)-3H imidazo[4,5-c]pyridine 293 132 WO 2013/151708 PCT/US2013/031055 [005351 Light brown solid (36.0 mg, 35.0% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.47 (s, 3H), 7.66 (dd, J=9.5Hz, J=5.5Hz, 1H), 7.68 (d, J=1.5Hz, 1H), 7.80 (q, J=3Hz, 1H), 7.91 (d, J=8.5Hz, 1H), 8.16 (brs, 1H), 8.56-8.64 (m, 2H), 8.70 (s, 1H), 8.82 (brs, 1H), 8.96 (s, IH), 9.10 (s, 1H), 14.41 (s, 1H); ESIMS found C 23 Hi 6
N
6 S m/z 409.4 (M+H). S N H N/ \NN
N
7 "N ~N H 295 [005361 N,N-Dimethyl-5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2 yl)-1 H-indazol-5 -yl)pyridin-3 -amine 295 [00537] Tan solid (28.8 mg, 0.066 mmol). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 3.09 (s, 6H), 7.43 (s, 1H), 7.73 (dd, J=4.5Hz, J=7.5Hz, 2H), 7.83 (d, J=8.5Hz, 1H), 7.90 (dd, J=1.5Hz, J=9Hz, 1H), 8.17 (brs, 1H), 8.19 (d, J=3Hz, 1H), 8.32 (s, 1H), 8.80 (brs, 1H), 8.82 (s, 1H), 8.87 (s, 1H), 13.81 (brs, 1H), 14.02 (s, 1H); ESIMS found
C
2 4
H
19
N
7 S m/z 438.1 (M+H).
S
7 N NH \N N> "NN H 301 [00538] N,N-Dimethyl-1-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2 yl)-1 H-indazol-5-yl)pyridin-3-yl)methanamine 301 [00539] Brown solid (45 mg, 43.3% yield). 'H NMR (DMSO-d,, 500 MHz) 6 ppm 2.24 (s, 6H), 3.59 (d, J=3Hz, 2H), 7.75 (dd, J=1OHz, J=3Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.93 (d, J=10.5Hz, 1H), 8.09 (s, 1H), 8.20 (d, J=5Hz, 1H), 8.54 (ABq, J=10.5Hz, 1H), 8.78 (s, 1H), 8.79 (s, 1H), 8.82 (s, 1H), 8.91 (s, 1H), 8.94 (d, J=2Hz, 1H), 13.69 (s, 1H), 14.01 (s, 1H); ESIMS found C 2 5
H
2 1
N
7 S m/z 452.0 (M+H). 133 WO 2013/151708 PCT/US2013/031055 S N H NN \ NH "N H 303 100540] 2-(5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-7 (thiophen-3-yl)-3H-imidazo[4,5-c]pyridine 303 [00541] Brown solid (92.8 mg, 52% yield). 'H NMR (DMSO-d 6 , 500 MHz) 8 ppm 1.39 (brs, 2H), 1.51 (brs, 4H), 2.43 (brs, 4H), 3.64 (s, 2H), 7.75 (t, J=4.5Hz, 1H), 7.85 (d, J=8Hz, 1H), 7.92 (d, J=9Hz, 1H), 8.08 (s, 1H), 8.19 (d, J=5Hz, 1H), 8.54 (s, 1H), 8.79 (s, 2H), 8.81 (s, 1H), 8.92 (s, 2H), 13.69 (brs, 1H), 14.01 (brs, 1H); ESIMS found
C
28
H
25
N
7 S m/z 492.3 (M+H). 0 NH N H NH N N N H 304 [00542] 3,3-Dimethyl-N-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2 yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 304 [005431 Brown solid (15 mg, 26.2% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.07 (s, 9H), 2.32 (s, 2H), 7.84 (dt, J=3Hz, J=5Hz, 1H), 7.90 (d, J=9Hz, 1H), 7.94 (d, J=8.5Hz, 1H), 8.23 (brs, 1H), 8.66 (brs, 1H), 8.73 (s, 1H), 8.76 (s, 1H), 8.84 (s, 1H), 8.94 (brs, 1H), 9.00 (brs, IH), 9.11 (brs, 1H), 10.30 (s, 1H), 14.42 (s, 1H), 14.93 (brs, 1H); ESIMS found C 2 8
H
25 N7OS m/z 508.2 (M+H). HN NH N 1N3 H 134 WO 2013/151708 PCT/US2013/031055 311 [005441 1 -Cyclopentyl-N-((5-(3 -(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin 2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine 311 [00545] Light brown solid (4.9 mg, 0.01 mmol, 5.4% yield). 1H NMR (DMSO d 6 , 500 MHz) 6 ppm 1.13-1.26 (m, 2H), 1.39-1.56 (m, 4H), 1.70 (brs, 2H), 2.01 (t, J=7.5Hz, 1H), 3.92 (s, 2H), 7.76 (dd, J=5Hz, J=3Hz, lH), 7.85 (d, J=8.5Hz, 1H), 7.92 (d, J=8.5Hz, 1H), 8.19 (brs, 1H), 8.22 (d, J=4.5Hz, 1H), 8.59 (s, 1H), 8.79 (s, 2H), 8.82 (s, iH), 8.92 (s, IH), 8.95 (s, 1H), 14.01 (brs, 1H); ESIMS found C 29
H
27
N
7 S m/z 506.0 (M+H). N N \ NH N N H 315 [00546] 7-(Furan-3-yl)-2-(5-(pyridin-3-yl)-IH-indazol-3-yl)- 3 H-imidazo[4,5 c]pyridine 315 [005471 Brown solid (68 mg, 77.5% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 7.44 (d, J=1.5Hz, 1H), 7.59 (dd, J=8Hz, J=5Hz, 1H), 7.87 (q, J=9Hz, 2H), 7.89 (s, 1H), 8.21 (dd, J=11Hz, J=2Hz, 1H), 8.63 (dd, J=9.5Hz, J=1.5Hz, iH), 8.71 (s, lH), 8.76 (s, 1H), 8.86 (d, J=10Hz, 2H), 9.03 (d, J=2.5Hz, 1H), 13.65 (s, iH), 14.01 (s, 1H); ESIMS found C 22
HI
4
N
6 0 m/z 379.1 (M+H). 0 NH NH N \N -~N H 319 [00548] N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5 yl)pyridin-3-yl)pivalamide 319 135 WO 2013/151708 PCT/US2013/031055 [00549] Tan solid (42.2 mg). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.30 (s, 9H), 7.83 (s, 1H), 7.86 (s, 2H), 8.59 (s, 1H), 8.71 (s, 2H), 8.77 (s, 1H), 8.83 (s, 1H), 8.87 (s, 1H), 8.91 (d, J=2Hz, 1H), 9.59 (s, 1H), 13.68 (brs, 1H), 14.02 (s, 1H); ESIMS found
C
27
H
23
N
7 0 2 m/z 478.3 (M+H). NH N 0 NH N NH N /'N -~N H 321 [005501 N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5 yl)pyridin-3-yl)-2-phenylacetamide 321 [00551] Beige solid (12.6 mg, 7.3% yield). 'H NMR (DMSO-d 6 , 500 MHz) 8 ppm 3.76 (s, 2H), 7.27 (t, J=7Hz, 1H), 7.30-7.40 (m, 4H), 7.45 (s, 1H), 7.77 (s, 1H), 7.84 (ABq, J=11.5Hz, 2H), 8.57 (s, 1H), 8.71 (s, 2H), 8.76 (s, 2H), 8.79 (s, 1H), 8.83 (s, 1H), 10.58 (s, 1H), 13.65 (s, 1H), 14.02 (s, 1H); ESIMS found C 30
H
2 1
N
7 0 2 m/z 512.1 (M+H). 0 NH N NNH Ny * I NN H 329 [00552] N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5 yl)pyridin-3-yl)pentanamide 329 [005531 Brown solid (70.0 mg, 0.15 mmol, 7.3% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.92 (t, J=7.5Hz, 3H), 1.37 (sex, J=7.5Hz, 2H), 1.63 (quin, J=7.5Hz, 2H), 2.41 (t, J=7.5Hz, 2H), 7.49 (brs, 1H), 7.82-7.93 (m, 3H), 8.60 (s, 1H), 8.70 (s, 1H), 8.73 (s, 1H), 8.82 (s, 2H), 8.88 (s, 1H), 8.96 (brs, 1H), 10.30 (s, 1H), 14.25 (s, 1H); ESIMS found C 2 7
H
23
N
7 0 2 m/z 478.3 (M+H). 136 WO 2013/151708 PCT/US2013/031055 0 NH O)(NH NH N N/ H 330 [005541 N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5 yl)pyridin-3-yl)cyclopropanecarboxamide 330 [00555] Light brown solid (10.6 mg, 4.2% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.82-0.86 (m, 4H), 1.86 (quin, J=5.5Hz, 1H), 7.49 (brs, 1H), 7.84-7.92 (m, 3H), 8.64 (brs, 1H), 8.71 (d, J=7.5Hz, 2H), 8.83 (d, J=9Hz, 2H), 8.89 (s, IH), 8.98 (brs, 1H), 10.64 (s, 1H), 14.28 (s, 1H); ESIMS found C 26
H
19
N
7 0 2 m/z 461.9 (M+H). o NH N/ N46 ,1 \NH N H 333 [00556] N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5 yl)pyridin-3-yl)cyclohexanecarboxamide 333 [00557] Brown solid (9.7 mg, 3.8% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 1.14-1.36 (m, 3H), 1.46 (dq, J=12.5Hz, J=2.5Hz, 2H), 1.49 (dq, J=12.5Hz, J=2.5Hz, 2H), 1.67 (d, J=12.5Hz, 1H), 1.79 (d, J=13Hz, 1H), 1.89 (d, J=12Hz, 2H), 2.00 (d, J=1OHz, 2H), 7.44 (brs, 1H), 7.80-7.87 (m, 3H), 8.57 (brs, 1H), 8.64-8.86 (m, 7H), 10.20 (s, 1H), 13.75 (brs, 1H), 14.04 (s, IH); ESIMS found C 29
H
25
N
7 0 2 m/z 504.3 (M+H). F F F N N N H 137 WO 2013/151708 PCT/US2013/031055 336 [005581 2-(5-(5-((3,3-Difluoropyrrolidin- 1 -yl)methyl)pyridin-3-yl)-1
H
indazol-3-yl)-7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine 336 [00559] Light brown solid (71.2 mg, 82.5% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.26 (sep, J=7Hz, 2H), 2.76 (t, J=7Hz, 2H), 2.95 (t, J=13Hz, 2H), 3.79 (s, 2H), 7.30 (dt, J=8.5Hz, J=2Hz, 1H), 7.60 (q, J=7.5Hz, 1H), 7.85 (d, J=9Hz, 1H), 7.91 (d, J=8.5Hz, 1H), 8.06 (s, 1H), 8.22 (d, J=7.5Hz, 1H), 8.42 (d, J=11.5Hz, 1H), 8.57 (s, 1H), 8.76 (s, 1H), 8.87 (s, 1H), 8.89 (s, 1H), 8.93 (d, J=2Hz, 1H), 13.77 (s, 1H), 14.03 (s, 1H); ESIMS found C 29
H
22
F
3
N
7 m/z 526.2 (M+H). F FN \ NH N N N N H 339 [00560] 2-(5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H indazol-3-yl)-7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridine 339 [005611 Brown solid (67.2 mg, 87.2% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.27 (sep, J=7Hz, 2H), 2.79 (t, J=7Hz, 2H), 2.98 (t, J=13Hz, 2H), 3.83 (s, 2H), 7.60 (dd, J=7.5, J=4.5Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 7.92 (d, J=8.5Hz, 1H), 8.08 (s, 1H), 8.57 (s, 1H), 8.67 (d, J=4Hz, 1H), 8.75 (brs, 2H), 8.89 (s, 2H), 8.93 (s, 1H), 9.59 (s, 1H), 13.79 (s, 1H), 14.02 (s, 1H); ESIMS found C 2 8
H
22
F
2
N
8 m/z 509.3 (M+H). FN N N N H 342 [005621 2-(5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-lH indazol-3-yl)-7-(piperidin-1-yl)-3H-imidazo[4,5-c]pyridine 342 138 WO 2013/151708 PCT/US2013/031055 [00563] Brown solid (50.4 mg, 42.1% yield). 1H NMR (DMSO-d 6 , 500 MHz) 8 ppm 1.60 (brs, 6H), 2.28 (sep, J=7Hz, 2H), 2.78 (t, J=7Hz, 2H), 2.96 (t, J=13Hz, 2H), 3.42 (brs, 1H), 3.48 (brs, 3H), 3.80 (s, 2H), 6.67 (s, 1H), 7.76-7.86 (m, 2H), 8.06 (s, 1H), 8.54 (s, 1H), 8.62 (s, 1H), 8.70 (s, 1H), 8.86 (d, J=2Hz, 1H), 12.88 (s, 1H), 13.79 (s, 1H); ESIMS found C 28
H
28
F
2
N
8 m/z 515.4 (M+H). F F NN N NN \/NH N H 346 [005641 2-(5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H indazol-3-yl)-7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridine 346 [00565] Brown solid (73.9 mg, 96.8% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 2.28 (sep, J=7Hz, 2H), 2.79 (t, J=7Hz, 2H), 2.98 (t, J=13Hz, 2H), 3.82 (s, 2H), 7.75 (dd, J=5Hz, J=3Hz, 1H), 7.85 (d, J=9Hz, 1H), 7.92 (d, J=8.5Hz, IH), 8.12 (s, 1H), 8.20 (d, J=4.5Hz, 1H), 8.57 (s, 1H), 8.79 (s, 2H), 8.82 (s, 1H), 8.93 (s, 1H), 8.96 (s, 1H), 13.69 (s, 1H), 14.01 (s, 1H); ESIMS found C 27
H
2 1
F
2
N
7 S m/z 514.4 (M+H). HN N N 0 NH F N N H H 349 [005661 N-(5-(3-(7-(3-( 2 -(Dimethylamino)ethylamino)-5-fluorophenyl)-3H imidazo[4,5-c]pyridin-2-yl)-IH-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide 349 [00567] Light brown solid (17.8 mg, 0.03 mmol, 50.7% yield). 1H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.97 (d, J=6.5Hz, 6H), 2.09 (s, 7H), 2.26 (d, J=7Hz, 2H), 2.31 (brs, 2H), 3.11 (t, J=6Hz, 2H), 5.79 (s, 1H), 6.44 (d, J=11Hz, 1H), 7.37 (s, 1H), 7.41 (d, J=9.5Hz, 1H), 7.77 (d, J=9Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 8.36 (s, 1H), 8.63 (s, 2H), 139 WO 2013/151708 PCT/US2013/031055 8.83 (s, 2H), 10.19 (s, 1H), 13.68 (brs, 1H), 14.01 (s, 1H); ESIMS found C 33
H
34
FN
9 0 m/z 592.3 (M+H). H N- N 0 7N 0 NH F N NH H 373 [005681 N-(5-(3-(7-(3-Fluoro-5-(methylsulfonamidomethyl)phenyl)-3H imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide 373 [00569] Light brown solid (13.8 mg, 0.023 mmol, 20.9% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.97 (d, J=6.5Hz, 6H), 2.11 (non, J=7.5Hz, 1H), 2.27 (d, J=7Hz, 2H), 2.89 (s, 3H), 4.29 (d, J=6Hz, 2H), 7.24 (d, J=8.5Hz, 1H), 7.71 (t, J=6Hz, 1H), 7.80 (d, J=9Hz, 1H), 7.87 (d, J=8.5Hz, 1H), 8.12 (s, 111), 8.39 (d, J=10.5Hz, 1H), 8.44 (s, 1H), 8.67 (s, 1H), 8.77 (s, 1H), 8.78 (s, 1H), 8.85 (s, 111), 8.88 (s, 1H), 10.20 (s, 1H), 13.80 (s, 1H), 14.05 (s, 1H); ESIMS found C 3 1
H
2 9
FN
8 0 3 S m/z 613.1 (M+H). NH NH \NN /N H 397 [005701 3-Methyl-N-(5-(3-(7-(thiophen-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl) 1H-indazol-5-yl)pyridin-3-yl)butanamide 397 [00571] Light brown solid (79.8 mg, 0.16 mmol, 62.2% yield). 'H NMR (DMSO-d 6 , 500 MHz) 6 ppm 0.98 (d, J=6.5Hz, 6H), 2.15 (non, J=7Hz, 11), 2.31 (d, J=7.5Hz, 2H), 7.26 (dd, J=5Hz, J=3.5Hz, 1H), 7.66 (d, J=5Hz, 1H), 7.86 (s, 211), 8.23 (brs, 1H), 8.61 (s, 1H), 8.70 (d, J=1.5Hz, 1H), 8.73 (d, J=2Hz, 1H), 8.77 (s, 1H), 8.81 (s, 1H), 9.01 (s, 1H), 10.28 (s, 1H), 13.77 (brs, 1H), 14.04 (s, 1H); ESIMS found
C
27
H
23
N
7 0S m/z 494.1 (M+H). 140 WO 2013/151708 PCT/US2013/031055 Example 2. [00572] The above synthesized compounds were screened using the assay procedure for Wnt activity described below. [00573] Reporter cell lines can be generated by stably transducing cells of cancer cell lines (e.g., colon cancer) with a lentiviral construct that include a wnt responsive promoter driving expression of the firefly luciferase gene. [005741 Lentiviral constructs can be made in which the SP5 promoter, a promoter having eight TCF/LEF binding sites derived from the SP5 promoter, is linked upstream of the firefly luciferase gene. The lentiviral constructs can also include a hygromycin resistance gene as a selectable marker. The SP5 promoter construct can be used to transduce SW480 cells, a colon cancer cell line having a mutated APC gene that generates a truncated APC protein, leading to de-regulated accumulation of -catenin. A control cell line can be generated using another lentiviral construct containing the luciferase gene under the control of the SV40 promoter which does not require -catenin for activation. [00575] Cultured SW480 cells bearing a reporter construct can be distributed at approximately 10,000 cells per well into 384 well multiwell plates. Compounds from a small molecule compound library can then be added to the wells in half-log dilutions using a three micromolar top concentration. A series of control wells for each cell type receive only buffer and compound solvent. Twenty-four hours after the addition of compound, reporter activity for luciferases can be assayed, for example, by addition of the BrightGlo luminescence reagent (Promega) and the Victor3 plate reader (Perkin Elmer). Readings can be normalized to DMSO only treated cells, and normalized activities can then be used in the IC 50 calculations. Table 2 shows the activity of selected indazole analogs. Table 2. Compound Wnt inhibition Compound Wnt inhibition Compound Wnt inhition 1 0.14-0.15 111 0.006 280 0.021 2 0.125 - 0.146 124 0.001 283 0008 3 0.083 - 0.179 127 0.014 286 0.569 4 0.013 - 0.040 136 0.035 289 0.002 141 WO 2013/151708 PCT/US2013/031055 5 0.067 - 0.098 154 0.373 291 0.002 6 0.010 - 0.013 163 0.296 293 0.191 7 0.214 - 0.463 164 >6 295 0.003 9 0.4 - 0.63 170 7 301 0.069 10 0.0034 - 0.009 173 0.845 303 1 11 0.0035 - 0.065 174 0.003 304 0.003 12 0.006 - 0.008 177 0.002 311 0.058 15 0.010 - 0.025 186 0.038 315 0.022 16 0.164 - 0.200 199 0.311 319 0.005 20 0.0014 - 0.0018 202 0.535 321 0.033 24 0.066 205 0.041 329 0.004 31 0.005 211 0.42 330 0.739 86 0.023 214 0.042 333 0.026 89 >10 217 0.039 336 0.055 90 0.012 247 0.002 339 0.039 91 0.002 252 0.650 342 0.020 94 0.011 257 0.095 346 0.002 97 0.001 260 0.315 349 0.022 99 >5 263 0.086 373 0.005 102 .004 268 >10 397 0.0001 104 0.007 274 >10 107 0.052 275 0.141 Example 3. [00576] Preparation of a parenteral suspension with a compound of Formula I for the treatment of bone/cartilage diseases. Table 3. Approximate solubility of a compound of Formula I Media Solubility (gg/mL) 0.01N HCI 5 0.1 N HCI 150 10mM PBS pH 7.4 <0.05 PBS/0.5%CMC/0.05%Tween80 0.3 PEG 400 8500 Propylene glycol 3700 EtOH 4500 Ethyl acetate 80 DCM 35 Captex 300 C8/C10 Triglyceride 50 [00577] Dynamic vapor sorption shows up to 17.2% water is absorbed, showing the hygroscopicity of a compound of Formula I. 142 WO 2013/151708 PCT/US2013/031055 Table 4. Differential scanning calorimetry results for a compound of Formula I Sample Dehydration Polymorphic change Melting Anhydrous API N/A 282.7-C & 17.4 J/g 361'C & 128.3 J/g Hydrated API 101'C & 309 J/g 283.7'C & 13.6 J/g 363'C & 117.9 J/g [00578] Preparation of a 220 ig/mL suspension in 0.5% CMC/0.05% tween 80 begins by dispensing 597 g + 1 g of Gibco IX PBS into the 1 L glass bottle. Using a 1 mL sterile syringe, measure 0.3 mL of Tween 80. In a weigh boat, weigh out 3 g + 0.1 g of Carboxymethyl Cellulose 7LXF PH (CMC). Start mixing the Tween80/PBS solution and slowly sprinkle the CMC into the 1 L bottle containing the PBS/Tween mixture (increase mixing speed as necessary). Once visually dispersed and the polymer is hydrated, start heating the container on a heating plate to promote phase inversion (turbidity). Once the solution is cool to the touch, filter NLT 120 mL into the 250 mL glass bottle. Weigh 27 mg of a compound of Formula I and suspend by mixing with the aid of 120 g of the sterile filtered CMC/tween solution. Fill 2 mL schott glass vials and 13 mm Flurotec coated stoppers (West Pharma) and autoclave the vials at 260'F for NLT 25 minutes. Particle size measurement (Table 4) was performed after autoclaving using a Horiba L-950. Table 5. D(v, 0.1) D(v, 0.5) D(v, 0.9) 220pig/mL suspension (autoclaved) 1.5tm 2.8pm 4.9pim Table 6. Osmolality pH Viscosity % purity Concentration (HPLC) (HPLC) 220pg/mL suspension 308 mOsm/kg 7.3 2.3 cP 99.0 226ptg/mL (autoclaved) Example 4. [00579] Preparation of a parenteral preparation with a compound of Formula I. 143 WO 2013/151708 PCT/US2013/031055 [005801 Weigh 10 mg of a compound of Formula I (or its salt) and dissolve with the aid of 10 mL of propylene glycol (USP grade), using aseptic techniques, sterile filter the solution using a millex GP syringe filter into a sterile glass (type II) container. Before parenteral administration, add I OmL of the above solution in propylene glycol to a vial containing 90 mL of sterile water, mix well. Example 5. [005811 Preparation of a suspension for intravitreal injection with a compound of Formula I. [00582] Weigh 10 mg of micronized compound of Formula I (median particle size of 5 pm) an added slowly while mixing to 100 mL of solution of 0.5% carboxymethyl cellulose (Aqualon 7LXF) and 0.05% tween 80 HP-LQ-MH (Croda) dissolved in PBS (Gibco, pH 7.4). The final suspension is loaded into 2 mL glass vials and terminally sterilized by autoclaving. [00583] It is also contemplated to heat sterilize the micronized compound of Formula I and aseptic mixing with the sterile filtered solution of 0.5% carboxymethyl cellulose (Aqualon 7LXF) and 0.05% tween 80 HP-LQ-MH (Croda) dissolved in PBS (Gibco, pH 7.4). [00584] Administration was performed using a 30G needle and a volume of approximately 50 pL for intravitreal injection in rabbits, the presence of the drug in the back of the eye (choroid/retina) was confirmed by LC/MS analysis after extraction using acetonitrile/ formic acid solution. Example 6. [005851 Composition for intratympanic injection with a compound of Formula [00586] Weigh 10 mg of a compound of Formula I and dissolve with the aid of 100 mL of propylene glycol (USP grade), using aseptic techniques, sterile filter the solution using a millex GP syringe filter into a sterile glass (type II) container. Before parenteral administration, add 10 mL of the above solution in propylene glycol to a vial containing 90 mL of sterile water, mix well. 144 WO 2013/151708 PCT/US2013/031055 [005871 Administration is performed using a 25G needle and a volume of approximately 200 ptL for intratympanic injection targeting the round window membrane. Example 7. [00588] Preparation of a composition for pulmonary delivery with a compound of Formula I for the treatment of pulmonary fibrosis. [00589] Weigh 100 mg of a compound of Formula I (or its salt) an added slowly while mixing to 100 mL of solution of 1.5% dextrose (or lactose) + 0.05% tyloxapol. The final solution is sterile filter the solution using a millex GP syringe filter. [00590] Administration is performed using a jet nebulizer (Pari LC plus) or an aerodose nebulizer. [00591] C57/B16 mice were dosed for 30 minutes via a nose only chamber (CH technology) at a flow rate of 15 LPM, particle size distribution and dose was measured by a 7 stage impactor (1 LPM) placed in one of the ports. A median aerosol particle size of 1.2 tm with a GSD of 1.8 [tm was obtained and a dosing rate of 1.8 ptM/min/mouse. Table 7. Concentrations of a compound of Formula I in Mice (C57/B16) Inhalation Conc. (ng/mL) Time Point (h) Plasma Lung Ratio 0.25 188 12600 67 2 132 7510 57 6 29.9 5225 175 23 453 2945 7 [00592] A diluted formulation of 0.5 mg/mL of compound of Formula I was nebulized for 10 and 30 minutes to C57/bl6 mice (animals with bleomycin induced pulmonary fibrosis via the administration of bleomycin via intratracheal administration), the compound of Formula I was delivered via a nose only chamber (CH technology) at a flow rate of 20 LPM daily for 14 days. At the end of the 14 days, the animals were tested for MMP-7 levels and the lungs were scored using the Ashcroft scoring system to evaluate pulmonary fibrosis. 145 Table 8. Treatment Ashcroft Scoring MMP-7 levels (ng/mL) PBS/no dose 0.25 10 Bleomycin/vehicle 3.04 13.6 Bleomycin/ 10 min aerosol 3.52 10.7 of a compound Formula I Bleomycin/ 30 min aerosol 2.08 9.4 of a compound Formula I Example 8. [00593] Preparation of a suspension of drug-eluting material with a compound of Formula I. [00594] Solution 1 (PLGA containing active): Weigh 425mg of PLGA 50:50 (PLGA 0.55-0.75, Lactel B6010-2P) + 4.5 mg of a compound of Formula I + 4mL of dichloromethane, mix well to dissolve. [00595] Solution 2 (1% PVA solution): Add 40 mL of DI water, then add 413 mg of polyvinyl alcohol (Sigma 87-89% hydrolyzed, PN 363170-25), mix to dissolve then sterile filter through a 0.22 p PES syringe filter (Millipore Millex GP). [00596] PLGA microparticle formation: Add 20 mL of solution 2 into a clean sterile container, while mixing (high speed mixing) slowly add the entire 4 mL of solution 1 to solution 2. [00597] The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. [00598] The reference to any prior art in this specification is not, and should not be taken as an acknowledgement or any form of suggestion that the referenced prior art forms part of the common general knowledge in Australia. 146

Claims (38)

1. A compound or pharmaceutically acceptable salt thereof having the structure of Fonnula I: R 2 / N N \ NH N SN H wherein: R 1 is -heteroarylR 3 R 4 ; R 2 is selected from the group consisting of H, pyridin-2-ylR 5 , pyridin-4-ylR 5 , thiopheneR 5 , furanR 5 , imidazoleR 5 , -heterocyclylR 6 and -arylR 7 ; R 3 is selected from the group consisting of H, -heterocyclylR, -NHC(=O)R 9 , NHSO2R 1 0 , -NR"R 1 2 and -(C 1-6 alkyl)NR" 'R 12 ; with the proviso that R 2 and R 3 are not both H; R 4 is 1-3 substituents each selected from the group consisting of H, Ci-9 alkyl, halide, CF3, -CN, OR 13 and amino; each R 5 is independently 1-4 substituents each selected from the group consisting of H, Ci-9 alkyl, halide, -CF3, -CN, OR 1 3 , -C(=O)R 1 , amino and -(C1-6 alkyl)NR" 1 R 12 ; each R 6 is independently 1-5 substituents each selected from the group consisting of H, Ci-9 alkyl, halide, -CF3, -CN, OR 13 and amino; each R 7 is independently 1-5 substituents each selected from the group consisting of Ci-9 alkyl, halide, -CF3, -CN, OR 13 , amino, -(C1-6 alkyl)NHSO2R 1 , -NR 12 (Ci-6alkyl)NR"R 12 and (Ci-6 alkyl)NR"R 1 2 ; R' is 1-5 substituents each selected from the group consisting of H, Ci-9 alkyl, halide, CF3, -CN, OR 13 and amino; R 9 is selected from the group consisting of Ci-9 alkyl, -heteroarylR, -heterocyclylR 6 , arylR 7 and -CH2carbocyclyl; 147 R 1 0 is selected from the group consisting of Ci-9 alkyl, -heteroarylR , -heterocyclylR 6 , arylR 7 , and -carbocyclylR 14 ; each R" is independently selected from Ci-6 alkyl; each R 12 is independently selected from the group consisting of H and Ci-6 alkyl; each R" and R 12 are optionally linked to form a five or six membered heterocyclyl ring; each R 1 3 is independently selected from the group consisting of H and Ci-6 alkyl; R 1 4 is 1-5 substituents each selected from the group consisting of H, Ci-9 alkyl, halide, CF3, -CN, OR 13 and amino.
2. The compound of claim 1 wherein R 1 is pyridineR 3 R 4 .
3. The compound of claim 2 wherein R 1 is pyridin-3-ylR 3 R 4 .
4. The compound of claim 3 wherein R 3 is -(Cl-6 alkyl)NR"R 12 .
5. The compound of claim 4 wherein R 3 is -(Ci- 2 alkyl)NR"R 12 , R 11 is -(Ci- 2 alkyl), R 12 is -(Ci- 2 alkyl) and R 4 is H.
6. The compound of claim 4 wherein R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring and R 4 is H.
7. The compound of claim 6 wherein the five or six membered heterocyclyl ring is substituted with 1-2 fluorines.
8. The compound of claim 3 wherein R 3 is -NHC(=O)R 9 .
9. The compound of claim 8 wherein R 4 is H and R 9 is selected from the group consisting of -(C 2 - 5 alkyl), phenyl, -carbocyclyl and -CH2carbocyclyl.
10. The compound of claim 3 wherein R 3 is -NHSO2R 1 0 .
11. The compound of claim 10 wherein R 4 is H and R 1 0 is selected from the group consisting of -(Ci- 4 alkyl) and phenyl.
12. The compound of claim 3 wherein R 3 is -heterocyclylRs.
13. The compound of claim 12 wherein R 4 is H and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
14. The compound of claim 3 wherein R 3 is H and R 4 is amino.
15. The compound according to any one of claims 3-14, in which R 2 is -pyridin-2-ylR 5 .
16. The compound according to any one of claims 3-14, in which R 2 is -pyridin-4-ylR 5 .
17. The compound according to any one of claims 3-14, in which R 2 is thiopheneR 5 .
18. The compound according to any one of claims 3-14, in which R 2 is -heterocyclylR 6 . 148
19. The compound according to any one of claims 3-14, in which R 2 is -heterocyclylR 6 , in which R 6 is selected from the group consisting of H, F and -(Ci- 4 alkyl), and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
20. The compound according to any one of claims 3-14, in which R 2 is -arylR 7 .
21. The compound according to any one of claims 3-14, in which R 2 is -phenylR 7 and R 7 is 1-2 fluorine atoms.
22. The compound according to any one of claims 3-14, in which R 2 is -phenylR 7 and R 7 is 2 substituents consisting of 1 fluorine atom and either -NR 12 (C1-6 alkyl)NR"R 12 or -(Ci-6 alkyl)NHS02R".
23. The compound of claim 1 having a structure selected from the group consisting of: N/ N/ N I N / N N / N ~N O NH 0 NH NH NN N N H H NH H HH\H N N-, Z N. N~ N N ,NN H H H H N/ NH11N NH NN N N N N N N H H H H F4 FN 0 'N- 0/NH0 H N N N N \NH \NH N. \ NH \ H /N NN -~N -N ~N -~N H H H H FF /N F /N 00 0 NH - 0 NH - N -... N N N-N \NH \NH \NH N NNH ~NN N ~N N H H H H 14 FF F F /N /N 0 NF0NH F~ 0 NH 0 NH -. F N N. N NH \NH N \NH I. \INH \NH Ny N. N' - N N' N~ N H H H H ONH 0 NH -. 0 NH -O 0 NH N N N N.\NH N.\NH N.NH N\NH N~-N ~ N N N. ~ Nw- N N N 'N ,N - N -~ N'- N -~ N H H H H F F F F N ~ NN O NH 0 NH - C 0 H -. 0 NH N. N N N N. NH N\NH N.\NH N.\NH N N ~N' - N/ N' N~ N H H H H F F FF / N /N /N O NH 0 NH --- 0 NH -0 NH N\NH NHN N N NHN \ NH / ,N N N- N /~ N/ N N/N H H H H F F N N F N F N~ O NH 0 NH -. 0 NH - 0 NH N N N N N. / N N N /N N~ N. H H H H FF O NH -- I \-N (DN I N N.\NH N. N NH N. N NHN N N- N N N- N N H H H H 150 HOo \> N/N \ N NN \ NHON H N NNHN N/N/N N N/N N. H \H N\H N\H 'NN 'N N /N N N N N F H H H H H/H H N/N/ NN/ -N N/ NI N N _N N N N N sN' '- N \ N HN NNH NH N N/ N/N N/N N NH NH NNH N N 'N 'NN~- .N X N / NN / / \N ~ N / N N / I N/ N NN H H H H HO HO HOHOO ZN /N)JN N/N HHO/ N N N N N. NH IN NH \NH ~ NH N/ N / N. N /N H H H H HO HO 0HO N /N N/N -1JNH -. NH H -.. NH NN N N ~ . NH ~ N NH N. NH N\NH -s" N. N/ N - N/ H H H H 0 HN/- N/N 0 HN N N /\ N NH -.. NH 'NH-- NH F 'ANH F NHF N N NN H H H H 151 N O 0 \/N 0 'i~ N 0 ~ N 0 'i N HH NHF NHF NHF NN N N N. \H N.\H \H N.\H N> NN CN CN 0 ~ 0 N 0~ N 0 N H N NH H NH N 7N N NN N N' H H H H HO- HO N N N N O0 \/ 0 0\ N/ D \ /N NI N. \F jj N. \F -IN. \N N. \NH N. NH NH N. N.HN ,N 6-0 - N ~ N -~ N H H H H HO F F N F 0HN N ' NH F NH, HN -.. - 0 NH N N. \NH N\NH N\NH N\NH N~ - N / N N/ H H H H H NN O', N H - 0 NH NH -. NH N NHNH NH N N H H H H 152 0NN N N N N.\NH N.\NH N.\NH \NH ,~ NI -- N, / N - N H H H H F F F HN HN OY H HNNH 2 N N N. \H 1 .\H N.\H N\NH N ,/N N ~ - ' ~N -N'- N H H H H /N F HN F F/\ NN ~ 0 N N N N N N\NH N\NH N\NH N\NH III \NH N. NN NN N / H H H H H N. NF FN /N 0 NH NH ~ 0:N N HN N NH N \N N N. N N. N NNH N.\H \H I H H1 F~ N F~ NF N F~ N NHN N NH H1 H N ~~ /NN/N/ 0 NH 0 NHl I N N N N N.\H N.\H N.\H N.\H F N F N H2N HT H HN 0 NH I 0 NH N H IN N N -~ N ~ N / N N/ N H H H H 153 F FF F/ /N /N /N N/ N HNN NHN N NNH ~ NN N' N\N H H H H F F F F N I- N.- HN N- O N /H N/N N NH 0H NH NH N NN -N/ N/ N ~ / N N H H H H F F F F /N N, /N 0H NH H NH N N- N N -N /~ N /~ N /~ N/ H H H H F F F F O H O NO 0N H N N N N \NH N \ H N \H N N \NH N N N N N "N N H H H H FF '~F F NN N OLN NH. 0H NHHHH NH N N N / N N N N / N H H H H NI N~\ / N \ N~\ / N 0 NH -~ 0 NH - NH, N11 NH N1 \N N \NH N\ NH N\ NH N N \'N N' N -~ N N-N H H H H H 154 H N 'N 0 N N N N' N NP NH / NH \NH N ONH NH NH NH N N N N N" N N/ N/ H H H H 0(:) N N-. N I N N \: N N H "" N \ H\ NN " -\ N NH NHN N N NN N. \N N N' N~ N H H H H NN N N \N \NHI _ NH1\NH NH &C NH NH N N /N N N 7 7 / N/ N /N N/ 0H NH HN HN-0 N 0 H N NYN N 2 NO N I. \\NH N \NH N.\NH N. NH - N- N N - N H H H H N / N / N N/ /N '~ HN / O NH . N H N NH. NN N N / N N /N N. / N NN N. N N N, H H H H H 155 N 0 H 0C NH 0 NH NHI N N\ NH N NNH ~ N N NNH N Ny- N N N' /~N H H H H N /N C /N /N / O N-- NH N N\NH N NH N\NH \NH N N ~ \ N N - N/ - N /~ N/ N~ N H H H H N/N /N N N -O 0 NH -- 0 NH -. 0 NH N N N N ~ y N Ny N H H H H 0) 2 H - N-.0 NH0N N N 1 \NH N \H N\NH ~ NH N N - N'- N XN/ N' H H H H N N N N \NHN 0N N\N N \N I NNy N N- N/ NH NP ~N - NN/ H H H H HNN PN I-P NH 2 NP. N NH N NH N NH N NH N/ \NH / N NN y N N N/ N/ N H H H H H 156 NN N N 0 0 NH N NH X NH NH ~ N N' H H H H CN P/N N/NN N/ N N N/N N CN/ ,NH "I_ N NP NP NP ~ . NH N\NH N.\NH N.\NH N.N ~N- N' 0 N' ~N/ H H H H NP/N N/N N NN CN /N CNNH / 0 NH -.. 0 NH -. 0 NH N N N N) N N.\NH N.\NH N.\NH N.\NH N. N N N Ny H H H H 02 NH N / N C7 N/ N NN N-N N HNN/ N N N NH N\NH N. \NH N. \NH N. N N- N H H H H ~N N-N/( CN N N P N. \NHNH \N \NNH N H H H H N ~ / N / N/ N Nw N.\ H H~ \H N\H .\H N.\H .N- 0NN N. NH NH 1 N HNHN N N N \N NN H H H H H 157 N NO / NH o H 0 NH 0 NH N'N /H NP NH \NHN N N N- N N / NN N N H H H H N N- //N NN N N N-N/I3 N 0 NH N N N N\NH N H \ NH NH I ~\N H N NN N N N/ H H H H N N / N NN/N 7 N/ N 7 7 N O NH -~0 NH -- 0 NH - N 0~H N N NP N \ H N \ H N / \NH N / \NH N'~~ NN- N ~N H H H H NN N N N - N N.VN N N //-NN ~ / NHN NHN/ 11NH \/NH N \NH NNH N~ NH OY N N ' \ N N /N -N ~N -~N ~NN H H H H NN N/N N/NN/ NH -N 2 ~H NNN N NH \ \NH N NH NNH N N N ~ N y N, NN/ N N,/N NN H H H H N / N N N -H N NN NN NN 0H NH NH N ~0 H N N N N H N N H N N N/ H H H H 158 N IN D N I NN NN NN NN NI N ININN N.\H \H .\H N.\H -_ /N - IN IN 1 N I H H H:N H HH0 N N NN/ o N~N N H 0\H N H NHN NH0 H N N N N' N.\H . \H N.\H N.\H I~N I N I~N ' I~N HI H H H -N NN HNNH N N N N N. \H . \H N. \H 1 .\H -~~~~~~~~ ,.N . ~N- N ~N ~ N' ,N/, IN N /NH 0 NH -~0 NH N 2 -. IN NP N, IN N. \NH N. \NH N\NH N\NH IN IN N IN ~N ~N ~N' IN\N H H H H /N /NN /N HN N I N -~0 NH NP NM N NP N. NH N\NH N\NH N\NH ,NI/N IN ~N I~N ~N ~N H H H H /N N /N/ NH NH NH 0NHH~NH N N N N H H H H 159 ON /N /NN N ~N 0 NH0NN N \NH \NH N. N NN N N /N N H H H H / N 7 N NH NN .2NH /N N HN N/ \NH N \NH N\NH NN '\NH N N. 0Y H HN /NHN 0 NH N. N 'N N H H H H S 7 ~\ /N~S NS y / ONH- N N . \H N.\H \ H \ H NZ\ N z- N. sN- N.N N NNN HH N H H H NH I 0NHHN N N N N N .\ N HN \ N HN N H .\ N N / N N H H H H 7 N N SOl /N S /N H s 7N 0NH N \ NH N~ NH N N N N N N/ NH N. H N.\H N.\H N1N H N N 7 - N. NHN NN/ N III I / N 7 N 7 N 7 N H H H H 160 N N H S / 0 NH /N \-IHNH NH N NH N N, \H N ,N -N w '- N'- N H H H H 0 NH 0 NH 0 N O'N H N N, N N. \H N.\H N. \H ~ NH N/1 N W ' N/ H H H H - Oy / N 0 7 / N N HN 5 7 / 0 NH 0 NH N N N N. NH N\NH N\NH ~ NH I ~ L- ~\N N~ 1 N - N ~ N -~ N N HH H H 0 7 /N 0 N 0 /N NH, . N 'N N N NH NH \NH N \NH \NH \NH\ NN ~ N NJ H H H H H 0 7 / 07 0 07 / 0 NH -O 0 NH 0 NH 0 NH N N N N. NH N\NH \NH N\NH 7 N N N N H H H H 0, NH/ N 0 7 /DN 0I/ N 0 7 / NH NH N HN NN/ N N/ H H H H 161 ~NH O /N 0 NH 0~ N0 NH 'N NH N\_N\ NH N NH NN NN '~"N N/- N H H H H YNN ON H NY H 7 0 7 / NH / N N~N Nr"N NHNN 0H NH H H H H F HN 0F/ YN F\/ F F F F N NN NN NN N HN \ N\NH N & \ NH I'NH NH NX X NNX N N' N IN IN _N N H H H H F F F F F Fp N N/N N ON NN 6 N N N N \NH N\NH N NH N NH N N~ N N N H H H H N / N ~ F F F S\ F 6N~ 6IIN N 6N / N N N, ~ NH N NH N\NH N N NH N N NN N~ N -~ N 7 N H H H H HNN NH F0 NH F H 2 NF F F N N N\ NH N NH N\ NH N NH N, \NH ~7 N \ ~ \ y-N N- N /N -N N/ - N' N N~ N -~ N H H H H H 162 HNHN HN N-HN N /NN HN F 'N"F0 NH N N NH \NH N N NH '-\NH N N N /N/N 0 ,NH F 0 NH F ,NH F "IN. F N N N NH N\NH \NH r*~ NH -~ N N/ N N/ - N H H H H HN HN N " H /NN N/ FN H .. 0 NF NN N Nb \NH N \NH N NH '\ NH N N ~ N 11: NN N' N , HH H H HNHN HN HN 0 NH F 0 NH F ~ 0 NH F 0 NH F N N N N N NHN\N NH N NH H H H H N H HN HN"~ HN'~ 0 NH F N HHN F NN F N HF N ' N N N>NH H N. \H N\H N\H 163 H N/ HN N-N /N /00 0 0 0 0 NH F - H 2 N F F N NN N N\ NH N NNH N N\NH N N \HNH N~ - N N N~ N H H H H H H N H HH N-. o N-. H 0 0~- /7~-0 o /NN /N N NN N/ N H H H H H HH NN H N 0 N 7 H H 0 0 0N 0 N/ 09 NHF NH F -.. F (DN F IN F NNN N NH N\H N NH N \H N \H / Ny N N /NN NN N - N ' hN ' N ~ H H H H H H H H H N /N /N/ / 0 0 -0 0 0;- 0-/S 0 NH F 0 NH F ~0 NH F O HF N N N \H \H NNH N\H - N N N H- H' H H'- N~ H H H H N /N N/ H //7-0 0'2N HF - 0 NH F 0 -- 0 NHF HN F 0_ \HHN H N NH /N/N /N J N -N -N - N x N H H H H 164 H N-/ "s NH, HN 0 O NHN F 0 NH N N H H N N.HN NH NN N \ N HN N y N. w~ N N / N H H H H /N/ \ - 0 NH N NN N N SS\ H N N \NH N N NNHN N' N' NN HH H H H N0 NH N N N. \N H N HN.NH N\H s N. \ N -sN - N N & ,NH H H H H 0NH S /N N NN -w NN N ~N H H H H N N N\NH NH N NNN.N N. NI N. N N-N'-N H H H H N N /N 0SH S -H HN SC N. \N NHN NH \ HNH N \NH NN N.N .N - N / N / N/ N/ H H H H 165 N FN N o NF 0 HF / s S S 0N NH NH, N N.~ ~~~~ \NNNH H N. \N .\N NHN N N N NH NH ~Nj N 'N X -~ - N'-~ N/ ~N' N' H H H H H HIrF/N F N F 0 NH S F / N S N /N N N N. \NH N. \NH \NH \NH -~N N' ' ~N -~ N H H H H 0 NH -- 0 NH NHF N N7 N N 1 N NH N \H N\NH N\NH N N , H H H H /) - O N N F-C '/N F /N F S S N/'Y0 NH 0 NH NH NN.\NH NNH HNHH H N N / N N N/ N H H H H F \/ N N. HN F S HN/ F CS 0l NH F-CS N H N N N/N N. \NH N. \H . \H N. HN ,N N - N / N/ N N N N H H H H 166 /N /N /N/N/ O NH \ NH 2 s si HN S N NN NH \NH NH N \NH \ NH N ~~ N N~ N- N N N / - N'- N'- N N ~ N H H H H H N N N 0 NH1 NH \NH \NH N\N H H H H ~ N /N NH NHN -~~ /N N N \NH \NH'I O NH NH NH NNH / / ,N - N N N -~ N /~ N/ H H H H NN/ NH s 0 NH -0 NH / 0 NH N N NHN \NH NH- NH 11\ NH N~ N'N HH H H NN NN NH N- \NH I - \ NH I"- \ NH ~~~ N' 'I~ ' N N N / N -N/ / H H H H 0 0 HN /\Ns/ HN s ~0 N 0 NH N NH N\NH N\NH N N N- 1\NH NN' / - N N N'/ H H H H 167 00 0 0 N s/NN ' 7 N NH, - HN N N HN N H N/ N 1 \NH l \~ NH \N \NH N N N~ Nl: - ~ N / N N -N 7 N 7N N ~N H H H H H 0 0 0 0 ,. /N s ' 7 N ' / 7/N 0 NH 0 CNH 0 NH 0 NH N \NH \ NH N\NH NH N~ N N / 7N / N N H H H H / NN NN 'NH O N \N N NSNP \H ~ - NH \NH N\NH "I/ N N 7 N / N / N' N/ H H H H 0 0 0 0 s Is s 0NH N O NH N~ 0 NH N ONHN NN N N II N N' N/ N 7 N/ H H H H 0 0 0 0 S ~ ~ N N/ S N N N NT N 9 HH I\NH \1NNH \1, NNH N H N 7 N 7 N 7 N/ N N / N /7 N/ H H H H 168 0 N- H HN N 0 N S F F0F Fp HN 6N /S CIIN I 6 F /N F \h NH NH \NH N, - -~ ' - N ~N H H H H 0 FF F / F F 6 F-N N NHNH H\NH NNI N -~N x H H and H
24. The compound of claim 1 having a structure selected from the group consisting of: N / N/ N -NN/N N N N N \N \NHN \N N\N __/ Ny IH H H HN N NN / N N N N \H \H \H \H \ N N Nj ,N ' N ~ N' 0~ N'NH \H H IH H N /N h0 NH0 NH0 N NN N N H N H N H N \H N F N. -~ N ~ N - N NN H H H H 169 FFF F N N N N N NH NN \NH N \ NH N '\ NH NN N N~ N -, N /~ N/' H H H H 0 INH -.-. 0 NH -. ONH N N NN N N H H H H FF/ F/\ /N e~ N / N N N\HN O N N X~N N, \NH N NN ~ N NH N H HH H NN 1 6- F / N FN N N N N N H\H HN\N H \H N NC N N - N Ny ,N N N - N/ N- N N H H H H F /NN\ N N N NN N N N N NH N \NH N \ NH N N NH N 'NN~N Ny N NN N ,N - N'/- N -~ N N~ N H H H H NN'\ NN /N OT N NH NN H I ~ NH NHN N N N N H H H H 170 N N N/N N/NOJN 0 NH 0 NHC NN N. N NHN.N "N NH'~ HN' , N' -~ N HHH H KII N/N N /N NN N 02'NH N/NN N1 \ NH N\NH N NHNH N j N N " N SN N'N HH H N.N NN 0D N H 0 NH 1/ 0 N N/N 0 NH NH I N/NH N(\NH N N. 0 NH I N. \H N. \H N\H 'N. N N P/N N' N N N N/ jt H NHNH NH N N~ N \N N/ HH H H NN NN N/ N N. /N /N N NHH 0 NH0 NH N~ 0 NH NN N N. NH ~- \N \ H N/.\NH HH H H H N>NN /N /N N /N /N /N S 7 N N N P NN N. NH N. \H N NH ". \NH N\NH " N ,N N N-N N HH H H H S 7 /N 7 /NSy / 171 HN~~~ N H ~ 0N NN N NH N NHN - ~NH N'N- NH H H H H F F 7 N 0 /N 0 /NN O NH O NH OY 0H NH N N N N N NH '- NH NH NN N ~ N "N N N \' - N H H H H H N. F F F F SHN 0 N NF NN/ N 0 NH F \ 0 NH F N CNN N N NH N NH N\N NH N N N N N N NI - N N' N N/ H H H H , an /N O NH N/\ NH N H
25. The compound of claim 1 having a structure selected from the group consisting of: F F 0_ N\ / \F \ / N N N N \ NH NP \ NH N \ NH N\N - N NHN "' NH "NH 1 NH \N N -N - N'- N- N H H H H F FFF NN 7 / N 0 NH O C H 0 NH -. ONH N N N N NH N NH N NH N NH N / N / N/ N H H H H 172 HN H HY H HH H 'NHN N NH I N H NH 0 NH N / NNF \ / HN NN H H H H F N 'N 7 /N N NN / O NH N NH NH 0 H N H N N N NH NH N. NH NH \NH N. N \ N- N.N . -N NN N -N/ H H H H H S /N N 7 S N y / H NH HH ," an H N\ NH I NH 0/ NH NH N NNN 6. A\pharacutca copsiin cmrsn. \NHraetial efeciv amonHf N.N NN- N ~- N H H H H SN0 N F F S NF N N N 0 NH -. NH N N N N N H H H H H /N \_ /N 0 NH F 0 NH N NH I~ N / H ,and H
26. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
27. A method of treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprising administering to the patient a therapeutically 173 effective amount of a compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein the patient is a human.
28. The method of claim 27, wherein the disorder or disease is selected from: diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, a mycotic or viral infection, a bone or cartilage disease, Alzheimer's disease, osteoarthritis, lung disease and cancer.
29. The method of claim 28, wherein the disorder or disease is pulmonary fibrosis.
30. The method of claim 28, wherein the disorder or disease is osteoarthritis.
31. The method of claim 28, wherein the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer leukemia, lymphoma, sarcoma and ovarian cancer.
32. The method of claim 28, wherein the compound inhibits one or more proteins in the Wnt pathway.
33. The method of claim 28, wherein the compound inhibits signaling induced by one or more Wnt proteins.
34. The method of either claim 32 or 33, wherein the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.
35. The method of claim 28, wherein the compound inhibits a kinase activity.
36. Use of a compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease in a patient, wherein the disorder or disease is selected from the group consisting of: diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, a mycotic or viral infection, a bone or cartilage disease, Alzheimer's disease, osteoarthritis, lung disease, and cancer, wherein the patient is a human.
37. The use of claim 36, wherein the disorder or disease is pulmonary fibrosis.
38. The use of claim 36, wherein the disorder or disease is osteoarthritis. 174
AU2013243899A 2012-04-04 2013-03-13 Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof Active AU2013243899B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2016203274A AU2016203274B2 (en) 2012-04-04 2016-05-19 Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261620107P 2012-04-04 2012-04-04
US61/620,107 2012-04-04
PCT/US2013/031055 WO2013151708A1 (en) 2012-04-04 2013-03-13 Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Related Child Applications (1)

Application Number Title Priority Date Filing Date
AU2016203274A Division AU2016203274B2 (en) 2012-04-04 2016-05-19 Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Publications (2)

Publication Number Publication Date
AU2013243899A1 AU2013243899A1 (en) 2014-04-24
AU2013243899B2 true AU2013243899B2 (en) 2016-02-25

Family

ID=49292798

Family Applications (2)

Application Number Title Priority Date Filing Date
AU2013243899A Active AU2013243899B2 (en) 2012-04-04 2013-03-13 Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof
AU2016203274A Active AU2016203274B2 (en) 2012-04-04 2016-05-19 Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
AU2016203274A Active AU2016203274B2 (en) 2012-04-04 2016-05-19 Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Country Status (32)

Country Link
US (9) US8673936B2 (en)
EP (3) EP2760285B1 (en)
JP (3) JP6167169B2 (en)
KR (1) KR102048107B1 (en)
CN (2) CN106892916A (en)
AU (2) AU2013243899B2 (en)
BR (1) BR112014023639B1 (en)
CA (1) CA2853703C (en)
CL (1) CL2014002511A1 (en)
CO (1) CO7230336A2 (en)
CY (1) CY1119485T1 (en)
DK (1) DK2760285T3 (en)
ES (1) ES2635386T3 (en)
HR (1) HRP20171322T1 (en)
HU (1) HUE033829T2 (en)
IL (2) IL234743A (en)
LT (1) LT2760285T (en)
MA (1) MA37450B1 (en)
ME (1) ME02832B (en)
MX (1) MX355435B (en)
MY (1) MY174896A (en)
NZ (3) NZ740938A (en)
PE (1) PE20142216A1 (en)
PH (3) PH12017500997A1 (en)
PL (1) PL2760285T3 (en)
PT (1) PT2760285T (en)
RS (1) RS56292B1 (en)
RU (2) RU2638932C2 (en)
SG (2) SG10201610539RA (en)
SI (1) SI2760285T1 (en)
WO (1) WO2013151708A1 (en)
ZA (3) ZA201406273B (en)

Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2987487B1 (en) * 2009-08-10 2020-10-07 Samumed, LLC Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
CN102821607B (en) 2009-12-21 2014-12-17 萨穆梅德有限公司 1H-pyrazolo[3,4-.Beta.]pyridines and therapeutic uses thereof
HUE041576T2 (en) 2011-09-14 2019-05-28 Samumed Llc Indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors
PH12017500997A1 (en) 2012-04-04 2018-02-19 Samumed Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
DK2770994T3 (en) 2012-05-04 2019-11-11 Samumed Llc 1H-PYRAZOLO [3,4-B] PYRIDINES AND THERAPEUTIC APPLICATIONS THEREOF
CA2897400A1 (en) 2013-01-08 2014-07-17 Samumed, Llc 3-(benzoimidazol-2-yl)-indazole inhibitors of the wnt signaling pathway and therapeutic uses thereof
GB201322334D0 (en) * 2013-12-17 2014-01-29 Agency Science Tech & Res Maleimide derivatives as modulators of WNT pathway
GB201322333D0 (en) 2013-12-17 2014-01-29 Agency Science Tech & Res WNT pathway modulators
KR20160135283A (en) * 2014-03-20 2016-11-25 사뮤메드, 엘엘씨 5-substituted indazole-3-carboxamides and preparation and use thereof
CN106458992B (en) * 2014-03-27 2019-03-15 默克专利股份公司 Pyridyl piperidine
EP3166627A1 (en) 2014-07-11 2017-05-17 Genentech, Inc. Notch pathway inhibition
WO2016040188A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040190A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof
WO2016040180A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040181A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040182A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine and therapeutic uses thereof
WO2016040185A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof
WO2016040184A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040193A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof
AU2016279474B2 (en) 2015-06-16 2021-09-09 Eisai R&D Management Co., Ltd. Anticancer agent
CN107614504B (en) 2015-06-23 2019-12-24 卫材R&D管理有限公司 Crystals of carboxamide compound
WO2017024025A1 (en) 2015-08-03 2017-02-09 Sunil Kumar Kc 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017023975A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof
US10206909B2 (en) 2015-08-03 2019-02-19 Samumed, Llc 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof
WO2017023988A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
US10392383B2 (en) 2015-08-03 2019-08-27 Samumed, Llc 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017023993A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-indol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
US10166218B2 (en) 2015-08-03 2019-01-01 Samumed, Llc 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof
WO2017023996A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
WO2017023972A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017023984A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof
US10604512B2 (en) 2015-08-03 2020-03-31 Samumed, Llc 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof
US10226448B2 (en) 2015-08-03 2019-03-12 Samumed, Llc 3-(1H-pyrrolo[3,2-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof
WO2017024015A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
US10285982B2 (en) 2015-08-03 2019-05-14 Samumed, Llc 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof
WO2017024003A1 (en) 2015-08-03 2017-02-09 Samumed, Llc 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017024021A1 (en) * 2015-08-03 2017-02-09 Samumed, Llc 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof
WO2017024010A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof
WO2017062688A1 (en) * 2015-10-08 2017-04-13 Suzhou Yunxuan Yiyao Keji Youxian Gongsi Wnt signaling pathway inhibitors and therapeutic applications thereof
CN105254613A (en) * 2015-10-08 2016-01-20 苏州云轩医药科技有限公司 Heterocyclic compound with Wnt signal path inhibitory activity and application thereof
US10450300B2 (en) 2015-10-08 2019-10-22 Suzhou Yunxuan Yiyao Keji Youxian Gongsi Wnt signaling pathway inhibitors and therapeutic applications thereof
EP3371186A1 (en) 2015-11-03 2018-09-12 Theravance Biopharma R&D IP, LLC Jak kinase inhibitor compounds for treatment of respiratory disease
CN108472290A (en) * 2015-11-06 2018-08-31 萨穆梅德有限公司 Treat osteoarthritis
SG11201810683VA (en) * 2016-06-01 2018-12-28 Samumed Llc Process for preparing n-(5-(3-(7-(3-fluorophenyl)-3h-imidazo[4,5-c]pyridin-2-yl)-1h-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide
MX2019004616A (en) 2016-10-21 2019-11-21 Samumed Llc Methods of using indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors.
WO2018085865A1 (en) * 2016-11-07 2018-05-11 Samumed, Llc Single-dose, ready-to-use injectable formulations
CA3059785A1 (en) 2017-05-01 2018-11-08 Theravance Biopharma R&D Ip, Llc Methods of treatment using a jak inhibitor compound
CN108314721B (en) * 2018-01-25 2021-06-22 首都医科大学 Human Wnt5a-NL nucleic acid recombinant as well as preparation method and application thereof
ES2945558T3 (en) 2018-02-23 2023-07-04 Biosplice Therapeutics Inc 5-heteroaryl substituted indazol-3-carboxamides and preparation and use thereof
US10759799B2 (en) 2018-06-15 2020-09-01 Samumed, Llc Indazole containing macrocycles and therapeutic uses thereof
WO2020150552A2 (en) 2019-01-17 2020-07-23 Samumed, Llc Methods of treating cartilage disorders through inhibition of clk and dyrk
WO2021121420A1 (en) * 2019-12-20 2021-06-24 江苏凯迪恩医药科技有限公司 Benzopyrazole compound and intermediate, preparation method, and application thereof
WO2022012058A1 (en) * 2020-07-16 2022-01-20 江苏凯迪恩医药科技有限公司 Fused ring compound, and intermediate thereof, preparation method therefor, and application thereof
KR20230087557A (en) 2020-10-13 2023-06-16 테바 체코 인더스트리즈 에스.알.오. solid form of lorecivint
WO2022256419A1 (en) * 2021-06-01 2022-12-08 University Of Maryland, Baltimore Dual wnt signaling pathway inhibitors and ampk activators for treatments of disease
CN114259565A (en) * 2021-12-28 2022-04-01 广州市妇女儿童医疗中心 Application of Wnt4 in preparing medicament for treating fibrosis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110034497A1 (en) * 2009-08-10 2011-02-10 Epitherix, Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Family Cites Families (174)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4164559A (en) 1977-09-21 1979-08-14 Cornell Research Foundation, Inc. Collagen drug delivery device
ES517193A0 (en) 1981-11-10 1983-12-01 Wellcome Found A PROCEDURE FOR THE PREPARATION OF NEW IMIDAZO DERIVATIVES (4,5-C) PIRIDINA.
US4474752A (en) 1983-05-16 1984-10-02 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
US4783443A (en) 1986-03-03 1988-11-08 The University Of Chicago Amino acyl cephalosporin derivatives
EP0410509A1 (en) 1989-07-25 1991-01-30 Duphar International Research B.V New substituted 1H-indazole-3-carboxamides
GB9414139D0 (en) 1994-07-13 1994-08-31 Smithkline Beecham Plc Novel compounds
US6440102B1 (en) 1998-07-23 2002-08-27 Durect Corporation Fluid transfer and diagnostic system for treating the inner ear
DE19853299C2 (en) 1998-11-19 2003-04-03 Thomas Lenarz Catheter for the application of medication in fluid spaces of the human inner ear
US6120484A (en) 1999-02-17 2000-09-19 Silverstein; Herbert Otological implant for delivery of medicament and method of using same
DE60026297T2 (en) 1999-05-21 2006-11-02 Bristol-Myers Squibb Co. PYRROLOTRIAZINE KINASEHEMMER
AU769350B2 (en) 1999-06-23 2004-01-22 Sanofi-Aventis Deutschland Gmbh Substituted benzimidazole
PE20010306A1 (en) 1999-07-02 2001-03-29 Agouron Pharma INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM USEFUL FOR THE INHIBITION OF PROTEIN KINASE
TWI262914B (en) 1999-07-02 2006-10-01 Agouron Pharma Compounds and pharmaceutical compositions for inhibiting protein kinases
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6967023B1 (en) 2000-01-10 2005-11-22 Foamix, Ltd. Pharmaceutical and cosmetic carrier or composition for topical application
YU54202A (en) 2000-01-18 2006-01-16 Agouron Pharmaceuticals Inc. Indazole compounds,pharmaceutical compositions,and methods for mediating or inhibiting cell proliferation
US6897231B2 (en) 2000-07-31 2005-05-24 Signal Pharmaceuticals, Inc. Indazole derivatives as JNK inhibitors and compositions and methods related thereto
US20050009876A1 (en) 2000-07-31 2005-01-13 Bhagwat Shripad S. Indazole compounds, compositions thereof and methods of treatment therewith
DE60120193T2 (en) 2000-09-15 2007-03-29 Vertex Pharmaceuticals Inc., Cambridge PYRAZOL COMPOUNDS AS PROTEIN KINASE HEMMER
AU2002222293A1 (en) 2000-12-19 2002-07-01 Smithkline Beecham P.L.C. Pyrazolo(3,4-c)pyridines as gsk-3 inhibitors
US20050192262A1 (en) 2001-03-13 2005-09-01 Tomas Hagstrom Treatment of tumours
ATE433751T1 (en) 2001-04-30 2009-07-15 Vertex Pharma INHIBITORS OF GSK-3 AND CRYSTAL STRUCTURES OF GSK-3BETA PROTEIN AND PROTEIN COMPLEXES
GB0115109D0 (en) 2001-06-21 2001-08-15 Aventis Pharma Ltd Chemical compounds
US7642278B2 (en) 2001-07-03 2010-01-05 Novartis Vaccines And Diagnostics, Inc. Indazole benzimidazole compounds
US7064215B2 (en) 2001-07-03 2006-06-20 Chiron Corporation Indazole benzimidazole compounds
EP1572072A4 (en) 2001-09-13 2009-04-01 Genesoft Inc Methods of treating infection by drug resistant bacteria
US7101884B2 (en) 2001-09-14 2006-09-05 Merck & Co., Inc. Tyrosine kinase inhibitors
US6648873B2 (en) 2001-09-21 2003-11-18 Durect Corp. Aural catheter system including anchor balloon and balloon inflation device
US6897208B2 (en) 2001-10-26 2005-05-24 Aventis Pharmaceuticals Inc. Benzimidazoles
EP1448557A4 (en) 2001-10-26 2005-02-02 Univ Connecticut Heteroindanes: a new class of potent cannabimimetic ligands
WO2003035065A1 (en) 2001-10-26 2003-05-01 Aventis Pharmaceuticals Inc Benzimidazoles and analogues and their use as protein kinases inhibitors
FR2831536A1 (en) 2001-10-26 2003-05-02 Aventis Pharma Sa NOVEL BENZIMIDAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE IN PARTICULAR AS KDR INHIBITORS
US20030187026A1 (en) 2001-12-13 2003-10-02 Qun Li Kinase inhibitors
US20040127492A1 (en) 2002-02-19 2004-07-01 Pharmacia Corporation Cyclic pyrazoles for the inhibition of mitogen activated protein kinase-activated protein kinase-2
BR0307796A (en) 2002-02-19 2004-12-21 Pharmacia Corp Tricyclic Pyrazole Derivatives for the Treatment of Inflammation
AU2003227741A1 (en) 2002-05-17 2003-12-02 Pharmacia Italia S.P.A. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
TW200406385A (en) 2002-05-31 2004-05-01 Eisai Co Ltd Pyrazole compound and pharmaceutical composition containing the same
US7449488B2 (en) 2002-06-04 2008-11-11 Schering Corporation Pyrazolopyrimidines as protein kinase inhibitors
AU2003240488A1 (en) 2002-06-04 2003-12-19 Neogenesis Pharmaceuticals, Inc. Pyrazolo` 1,5a! pyrimidine compounds as antiviral agents
US20050282733A1 (en) 2002-06-27 2005-12-22 Prins Johannes B Differentiation modulating agents and uses therefor
GB0218625D0 (en) 2002-08-10 2002-09-18 Astex Technology Ltd Pharmaceutical compounds
FR2845382A1 (en) 2002-10-02 2004-04-09 Sanofi Synthelabo INDAZOLECARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THERAPEUTICS
EP1611131B1 (en) 2003-02-27 2010-09-15 Palau Pharma, S.A. Pyrazolopyridine derivates
US7135575B2 (en) 2003-03-03 2006-11-14 Array Biopharma, Inc. P38 inhibitors and methods of use thereof
WO2005012301A1 (en) 2003-07-03 2005-02-10 Aventis Pharmaceuticals Inc. Pyrazoloisoquinoline derivatives as kinase inhibitors
TWI372050B (en) 2003-07-03 2012-09-11 Astex Therapeutics Ltd (morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles
EP1651612B9 (en) 2003-07-22 2012-09-05 Astex Therapeutics Limited 3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators
US7008953B2 (en) 2003-07-30 2006-03-07 Agouron Pharmaceuticals, Inc. 3, 5 Disubstituted indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation
GT200400136A (en) 2003-07-30 2005-05-02 3.5-DISPOSED INDAZOL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND METHODS TO INTERVENE IN OR INHIBIT CELLULAR APPROVALIFERATION.
US20050090529A1 (en) 2003-07-31 2005-04-28 Pfizer Inc 3,5 Disubstituted indazole compounds with nitrogen-bearing 5-membered heterocycles, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation
WO2005014554A1 (en) 2003-08-08 2005-02-17 Astex Therapeutics Limited 1h-indazole-3-carboxamide compounds as mapkap kinase modulators
JP5095216B2 (en) 2003-11-14 2012-12-12 ローラス セラピューティクス インコーポレーテッド Arylimidazoles and their use as anticancer agents
EP1532980A1 (en) 2003-11-24 2005-05-25 Novo Nordisk A/S N-heteroaryl indole carboxamides and analogues thereof, for use as glucokinase activators in the treatment of diabetes
FR2864084B1 (en) 2003-12-17 2006-02-10 Aventis Pharma Sa NOVEL ORGANOPHOSPHORUS DERIVATIVES OF INDAZOLES AND THEIR USE AS MEDICAMENTS
FR2867778B1 (en) 2004-03-16 2006-06-09 Sanofi Synthelabo USE OF INDAZOLECARBOXAMIDE DERIVATIVES FOR THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT AND PREVENTION OF MALARIA
KR101176670B1 (en) 2004-03-25 2012-08-23 메모리 파마슈티칼스 코포레이션 Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof
EP1742944B1 (en) 2004-04-22 2010-11-10 Memory Pharmaceuticals Corporation Indoles, 1h-indazoles, 1,2-benzisoxazoles, 1,2-benzoisothiazoles, and preparation and uses thereof
EP1753428A4 (en) 2004-05-14 2010-09-15 Abbott Lab Kinase inhibitors as therapeutic agents
EP1781653A1 (en) 2004-07-05 2007-05-09 Astex Therapeutics Limited 3,4-disubstituted pyrazoles as cyclin dependent kinases (cdk) or aurora kinase or glycogen synthase 3 (gsk-3) inhibitors
US7626021B2 (en) 2004-07-27 2009-12-01 Sgx Pharmaceuticals, Inc. Fused ring heterocycle kinase modulators
US7452993B2 (en) 2004-07-27 2008-11-18 Sgx Pharmaceuticals, Inc. Fused ring heterocycle kinase modulators
AR050188A1 (en) 2004-08-03 2006-10-04 Uriach Y Compania S A J CONDENSED HETEROCICLIC COMPOUNDS USED IN THERAPY AS INHIBITORS OF P38 KINASES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2006024945A1 (en) 2004-09-03 2006-03-09 Pfizer Inc. Pharmaceutical compositions comprising a cdk inhibitor
US7652043B2 (en) 2004-09-29 2010-01-26 The Johns Hopkins University WNT pathway antagonists
US20060116519A1 (en) 2004-11-17 2006-06-01 Agouron Pharmaceuticals, Inc. Synthesis of 5-bromo-4-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester
WO2006054143A1 (en) 2004-11-17 2006-05-26 Pfizer Inc. Polymorphs of {5-[3-(4,6-difluoro-1h-benzoimidazol-2-yl)-1h-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-amine
WO2006063302A2 (en) 2004-12-10 2006-06-15 Wyeth Variants of glycogen synthase kinase 3 and uses thereof
US20060142247A1 (en) 2004-12-17 2006-06-29 Guy Georges Tricyclic heterocycles
TWI427077B (en) * 2004-12-30 2014-02-21 Astex Therapeutics Ltd Pyrazole compound and use thereof and pharmaceutical composition containing the same
EP1861161A4 (en) 2005-01-24 2012-05-16 Neurosystec Corp Apparatus and method for delivering therapeutic and/or other agents to the inner ear and to other tissues
US7541367B2 (en) 2005-05-31 2009-06-02 Janssen Pharmaceutica, N.V. 3-benzoimidazolyl-pyrazolopyridines useful in treating kinase disorders
KR101011956B1 (en) 2005-08-25 2011-01-31 에프. 호프만-라 로슈 아게 P38 map kinase inhibitors and methods for using the same
US8106066B2 (en) 2005-09-23 2012-01-31 Memory Pharmaceuticals Corporation Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof
UY29825A1 (en) 2005-10-03 2007-05-31 Astrazeneca Ab SUBSTITUTED DERIVATIVES OF 3H-IMIDAZOL- (4.5 B (BETA)) PIRIDINA-2-IL BENZOATES AND BENZAMIDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND APPLICATIONS
AR057987A1 (en) 2005-11-24 2008-01-09 Astrazeneca Ab CB1 AGONIST COMPOUNDS (CANNABINOID RECEPTOR)
JP5474354B2 (en) 2005-12-30 2014-04-16 アステックス、セラピューティックス、リミテッド Pharmaceutical compounds
GB0602178D0 (en) 2006-02-03 2006-03-15 Merck Sharp & Dohme Therapeutic treatment
BRPI0709082A2 (en) 2006-03-23 2011-06-28 Hoffmann La Roche substituted indazole derivatives, their manufacture and use as pharmaceutical agents
MX2008012482A (en) 2006-03-31 2008-10-10 Abbott Lab Indazole compounds.
CA2654358A1 (en) 2006-06-22 2007-12-27 Biovitrum Ab (Publ) Pyridine and pyrazine derivatives as mnk kinase inhibitors
EP2049106A2 (en) 2006-07-14 2009-04-22 Astex Therapeutics Limited Pharmaceutical combinations
WO2008048502A1 (en) 2006-10-17 2008-04-24 Janssen Pharmaceutica N.V. Substituted pyrazole kinase inhibitors
WO2008061109A2 (en) 2006-11-15 2008-05-22 Forest Laboratories Holdings Limited Indazole derivatives useful as melanin concentrating receptor ligands
EP1932830A1 (en) 2006-12-11 2008-06-18 The Genetics Company, Inc. Sulfonamides and their use as a medicament
EP1932834B1 (en) 2006-12-11 2011-04-27 The Genetics Company, Inc. Aromatic 1,4-DI-Carboxylamides and their use
CL2007003609A1 (en) 2006-12-14 2008-07-25 Bayer Schering Pharma Ag COMPOUNDS DERIVED FROM REPLACED DIHYDROPIRIDINES; PREPARATION PROCESS; INTERMEDIARY COMPOUNDS; PHARMACEUTICAL COMPOSITION; PROCESS TO PRODUCE PHARMACEUTICAL COMPOSITION; AND USE IN THE TREATMENT OF A DISEASE IMPROVED WITH INHIBITION
EP2078020A4 (en) 2007-04-10 2011-10-19 Sgx Pharmaceuticals Inc Fused ring heterocycle kinase modulators
WO2008137408A1 (en) 2007-04-30 2008-11-13 Genentech, Inc. Pyrazole inhibitors of wnt signaling
US8129519B2 (en) 2007-05-10 2012-03-06 Cholody Wieslaw M Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof
US20080287452A1 (en) 2007-05-16 2008-11-20 Wyeth Heteroaryl/aryl pyrimidine analogs and their use as agonists of the wnt-beta-catenin cellular messaging system
US8304408B2 (en) 2007-05-24 2012-11-06 The Regents Of The University Of California Wnt signaling inhibitors, and methods for making and using them
TW200908968A (en) 2007-05-29 2009-03-01 Sgx Pharmaceuticals Inc Substituted pyrrolopyridines and pyrazolopyridines as kinase modulators
US20090099062A1 (en) 2007-05-31 2009-04-16 Ethan Lee Pyrvinium For The Treatment of Cancer
KR20100032886A (en) 2007-06-08 2010-03-26 아보트 러보러터리즈 5-heteroaryl substituted indazoles as kinase inhibitors
US8648069B2 (en) 2007-06-08 2014-02-11 Abbvie Inc. 5-substituted indazoles as kinase inhibitors
EP2157859A4 (en) 2007-06-19 2011-01-12 Takeda Pharmaceutical Indazole compounds for activating glucokinase
FR2917735B1 (en) 2007-06-21 2009-09-04 Sanofi Aventis Sa NEW SUBSTITUTED INDAZOLES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
US20090069288A1 (en) 2007-07-16 2009-03-12 Breinlinger Eric C Novel therapeutic compounds
EP2182984A2 (en) 2007-08-02 2010-05-12 Nerviano Medical Sciences S.r.l. A morpholinyl anthracycline derivative combined with protein kinase inhibitors
RU2350271C1 (en) 2007-08-20 2009-03-27 Федеральное государственное учреждение "Российский научный центр "Восстановительная травматология и ортопедия" имени академика Г.А. Илизарова Федерального агентства по высокотехнологичной медицинской помощи", ФГУ "РНЦ "ВТО" им. акад. Г.А. Илизарова Росмедтехнологий" Treatment method of early stages of hip joint osteoarthrosis
EP2185556A1 (en) 2007-08-27 2010-05-19 Wyeth a Corporation of the State of Delaware Imidazopyridine analogs and their use as agonists of the wnt-beta-catenin cellular messaging system
WO2009061345A2 (en) 2007-11-07 2009-05-14 Cornell Research Foundation, Inc. Targeting cdk4 and cdk6 in cancer therapy
KR20100101666A (en) 2007-12-19 2010-09-17 제넨테크, 인크. 8-anilinoimidazopyridines and their use as anti-cancer and/or anti-inflammatory agents
CA2726164A1 (en) * 2008-05-27 2009-12-23 The Board Of Regents Of The University Of Texas System Wnt protein signalling inhibitors
KR101061599B1 (en) 2008-12-05 2011-09-02 한국과학기술연구원 Novel indazole derivatives that are protein kinase inhibitors for the treatment of abnormal cell growth diseases, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same as active ingredients
CN101440092B (en) 2008-12-25 2010-11-17 浙江大学 2-indazole-4-aza indole-5-amino derivatives, and preparation and use thereof
AR076126A1 (en) 2009-03-18 2011-05-18 Schering Corp BICYCLE COMPOUNDS AS INHIBITORS OF DIACILGLICEROL ACILTRANSFERASA
CA2755768A1 (en) 2009-03-23 2010-09-30 Merck Sharp & Dohme Corp. P2x3, receptor antagonists for treatment of pain
EP3406260B1 (en) 2009-05-13 2020-09-23 The University of North Carolina at Chapel Hill Cyclin dependent kinase inhibitors and methods of use
UA110324C2 (en) 2009-07-02 2015-12-25 Genentech Inc Jak inhibitory compounds based on pyrazolo pyrimidine
JP2013500267A (en) 2009-07-23 2013-01-07 ヴァンダービルト ユニバーシティー Substituted benzimidazole sulfonamides and substituted indole sulfonamides as mGLuR4 enhancers
EP2464231A4 (en) * 2009-08-10 2013-02-06 Samumed Llc Indazoles as wnt/b-catenin signaling pathway inhibitors and therapeutic uses thereof
WO2011050245A1 (en) 2009-10-23 2011-04-28 Yangbo Feng Bicyclic heteroaryls as kinase inhibitors
CN102821607B (en) 2009-12-21 2014-12-17 萨穆梅德有限公司 1H-pyrazolo[3,4-.Beta.]pyridines and therapeutic uses thereof
MX2012007329A (en) 2009-12-21 2012-10-15 Array Biopharma Inc Substituted n-(1h-indazol-4-yl)imidazo[1, 2-a]pyridine-3- carboxamide compounds as cfms inhibitors.
KR101792895B1 (en) 2010-04-06 2017-11-02 피터 맥칼룸 캔서 인스티튜트 Radioprotector compounds and method
DE102010043379A1 (en) 2010-11-04 2012-05-10 Bayer Schering Pharma Aktiengesellschaft Substituted 6-fluoro-1H-pyrazolo [4,3-b] pyridines and their use
US20130310379A1 (en) 2010-11-19 2013-11-21 Constellation Pharmaceuticals Modulators of methyl modifying enzymes, compositions and uses thereof
EA024059B1 (en) 2011-01-13 2016-08-31 Новартис Аг Heterocyclic derivatives and their use in the treatment of neurological disorders
US8889684B2 (en) 2011-02-02 2014-11-18 Boehringer Ingelheim International Gmbh Azaindolylphenyl sulfonamides as serine/threonine kinase inhibitors
WO2012129562A2 (en) 2011-03-24 2012-09-27 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
EP2694060A4 (en) 2011-04-01 2014-09-10 Univ Utah Res Found Substituted 3-(1h-benzo{d}imidazol-2-yl)-1h-indazole-analogs as inhibitors of the pdk1 kinase
US11325904B2 (en) 2011-08-02 2022-05-10 Buck Institute For Research On Aging Tropinol esters and related compounds to promote normal processing of APP
JP6133291B2 (en) 2011-08-12 2017-05-24 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト Pyrazolo [3,4-c] pyridine compounds and methods of use
CN103889976A (en) 2011-08-12 2014-06-25 弗·哈夫曼-拉罗切有限公司 Indazole compounds, compositions and methods of use
MX359032B (en) 2011-09-01 2018-09-12 Hoffmann La Roche Pyrrolopyrazine kinase inhibitors.
HUE041576T2 (en) 2011-09-14 2019-05-28 Samumed Llc Indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors
EP2810198B1 (en) 2012-01-30 2023-07-12 Universiteit Gent Anti-invasive compounds
CA2868302A1 (en) 2012-03-23 2013-09-26 Dennis M. Brown Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
PH12017500997A1 (en) 2012-04-04 2018-02-19 Samumed Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
US9056874B2 (en) 2012-05-04 2015-06-16 Novartis Ag Complement pathway modulators and uses thereof
MX2014013430A (en) 2012-05-04 2015-04-14 Basf Se Substituted pyrazole-containing compounds and their use as pesticides.
DK2770994T3 (en) 2012-05-04 2019-11-11 Samumed Llc 1H-PYRAZOLO [3,4-B] PYRIDINES AND THERAPEUTIC APPLICATIONS THEREOF
CA2897400A1 (en) 2013-01-08 2014-07-17 Samumed, Llc 3-(benzoimidazol-2-yl)-indazole inhibitors of the wnt signaling pathway and therapeutic uses thereof
CN105188704B (en) 2013-01-16 2017-09-19 西格诺药品有限公司 Substituted Pyrrolopyrimidine compounds, its composition and use its treatment method
US9327886B2 (en) 2013-03-13 2016-05-03 Bayer Healthcare Llc Vial container with collar cap
EP3269716B1 (en) 2013-03-14 2020-09-16 Galapagos N.V. Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
FR3011239A1 (en) 2013-10-01 2015-04-03 Univ Claude Bernard Lyon NOVEL DERIVATIVES COMPRISING A PYRAZOLE GROUP AND AN INDOLE GROUP, USEFUL AS INHIBITORS OF KINASE GSK3
KR20160135283A (en) 2014-03-20 2016-11-25 사뮤메드, 엘엘씨 5-substituted indazole-3-carboxamides and preparation and use thereof
WO2016040184A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040188A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040190A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof
US9538272B2 (en) 2014-09-08 2017-01-03 Apple Inc. Acoustic mesh and methods of use for electronic devices
WO2016040185A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof
WO2016040193A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof
WO2016040181A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040182A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine and therapeutic uses thereof
WO2016040180A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2017024010A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof
US20180228780A1 (en) 2015-08-03 2018-08-16 Samumed, Llc 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof
WO2017024015A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
US10392383B2 (en) 2015-08-03 2019-08-27 Samumed, Llc 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017023984A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof
US10285982B2 (en) 2015-08-03 2019-05-14 Samumed, Llc 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof
WO2017024021A1 (en) 2015-08-03 2017-02-09 Samumed, Llc 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof
US10206909B2 (en) 2015-08-03 2019-02-19 Samumed, Llc 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof
WO2017023973A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-indol-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
WO2017023981A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
US10226448B2 (en) 2015-08-03 2019-03-12 Samumed, Llc 3-(1H-pyrrolo[3,2-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof
US10166218B2 (en) 2015-08-03 2019-01-01 Samumed, Llc 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof
WO2017023993A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-indol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017024003A1 (en) 2015-08-03 2017-02-09 Samumed, Llc 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017023988A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017023975A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof
WO2017023996A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
US10604512B2 (en) 2015-08-03 2020-03-31 Samumed, Llc 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof
WO2017023972A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
CN108472290A (en) 2015-11-06 2018-08-31 萨穆梅德有限公司 Treat osteoarthritis
AR108325A1 (en) 2016-04-27 2018-08-08 Samumed Llc ISOQUINOLIN-3-IL CARBOXAMIDS AND PREPARATION AND USE OF THE SAME
SG11201810683VA (en) 2016-06-01 2018-12-28 Samumed Llc Process for preparing n-(5-(3-(7-(3-fluorophenyl)-3h-imidazo[4,5-c]pyridin-2-yl)-1h-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide
MX2019004616A (en) 2016-10-21 2019-11-21 Samumed Llc Methods of using indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors.
WO2018085865A1 (en) 2016-11-07 2018-05-11 Samumed, Llc Single-dose, ready-to-use injectable formulations
EP3813826A4 (en) 2018-06-26 2022-07-06 BioSplice Therapeutics, Inc. Methods of treating cancer using a clk inhibitor
WO2020150552A2 (en) 2019-01-17 2020-07-23 Samumed, Llc Methods of treating cartilage disorders through inhibition of clk and dyrk

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110034497A1 (en) * 2009-08-10 2011-02-10 Epitherix, Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HU, Y. ET AL., Bioorganic & Medicinal Chemistry Letters, 2011, Vol. 21, pages 4758-4761 *

Also Published As

Publication number Publication date
US20190071440A1 (en) 2019-03-07
RU2014144309A (en) 2016-05-27
JP6401345B2 (en) 2018-10-10
PE20142216A1 (en) 2015-01-12
EP2760285A1 (en) 2014-08-06
PH12017501588A1 (en) 2018-07-02
RU2638932C2 (en) 2017-12-19
MA37450A1 (en) 2016-07-29
ES2635386T3 (en) 2017-10-03
US10407425B2 (en) 2019-09-10
PH12014502183A1 (en) 2014-12-10
LT2760285T (en) 2017-10-10
US20140179696A1 (en) 2014-06-26
EP2760285A4 (en) 2015-04-22
PL2760285T3 (en) 2017-12-29
EP2760285B1 (en) 2017-06-21
WO2013151708A1 (en) 2013-10-10
US20150152105A1 (en) 2015-06-04
ZA201906377B (en) 2023-04-26
BR112014023639A2 (en) 2017-06-20
ME02832B (en) 2018-01-20
PH12017500997A1 (en) 2018-02-19
KR20140143796A (en) 2014-12-17
US20230013144A1 (en) 2023-01-19
NZ629323A (en) 2016-12-23
PH12014502183B1 (en) 2014-12-10
KR102048107B1 (en) 2019-11-22
CA2853703A1 (en) 2013-10-10
CO7230336A2 (en) 2015-03-31
IL254935A0 (en) 2017-12-31
CN104202984B (en) 2017-04-05
US11697649B2 (en) 2023-07-11
SI2760285T1 (en) 2017-11-30
CN106892916A (en) 2017-06-27
MY174896A (en) 2020-05-20
JP6167169B2 (en) 2017-07-19
US9994563B2 (en) 2018-06-12
EP3284744B1 (en) 2021-05-05
MX355435B (en) 2018-04-18
MX2014011996A (en) 2014-11-10
CY1119485T1 (en) 2018-03-07
RS56292B1 (en) 2017-12-29
EP3284744A1 (en) 2018-02-21
US20130267495A1 (en) 2013-10-10
HRP20171322T1 (en) 2017-10-20
US8664241B2 (en) 2014-03-04
US10947228B2 (en) 2021-03-16
SG11201406310RA (en) 2014-11-27
JP2018188479A (en) 2018-11-29
US20160297812A1 (en) 2016-10-13
AU2013243899A1 (en) 2014-04-24
CA2853703C (en) 2019-01-22
SG10201610539RA (en) 2017-02-27
US8673936B2 (en) 2014-03-18
IL234743A (en) 2017-10-31
CN104202984A (en) 2014-12-10
AU2016203274A1 (en) 2016-06-09
US20240116927A1 (en) 2024-04-11
US8987298B2 (en) 2015-03-24
ZA201906378B (en) 2022-12-21
EP3915988A1 (en) 2021-12-01
HUE033829T2 (en) 2018-01-29
PT2760285T (en) 2017-08-16
DK2760285T3 (en) 2017-09-18
RU2682245C1 (en) 2019-03-18
US9199991B2 (en) 2015-12-01
MA37450B1 (en) 2018-03-30
NZ727358A (en) 2018-10-26
NZ740938A (en) 2019-11-29
ZA201406273B (en) 2019-12-18
JP2015512443A (en) 2015-04-27
US20140005170A1 (en) 2014-01-02
CL2014002511A1 (en) 2015-01-09
JP2017214393A (en) 2017-12-07
US20200190082A1 (en) 2020-06-18
BR112014023639B1 (en) 2022-03-29
AU2016203274B2 (en) 2017-09-14

Similar Documents

Publication Publication Date Title
US11697649B2 (en) Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof
US10342788B2 (en) 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)